Quinoline and quinazoline derivatives having affinity for 5ht1-type receptors

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof are provided:  
                 
 
wherein R 1 , m, X, R 2 , n, W, p, Y, Z, R 3 , R 4 , R 5  and q have the meanings as defined in the description. Methods of preparation and uses thereof in therapy, particularly for CNS disorders such as depression or anxiety, are also disclosed.

This application is a continuation of Application No. 10/565,066, filedJan. 17, 2006, which is a 371 of International Application No.PCT/EP2004/008000, filed 15 Jul. 2004, which claims benefit of GreatBritain Application No. GB 0316915.8, filed 18 Jul. 2003.

The present invention relates to novel compounds, processes for theirpreparation, pharmaceutical compositions containing the same and theiruse as medicaments in the treatment of CNS and other disorders.

A novel series of compounds has now been found that possess highaffinity for 5-HT₁ type receptors and/or are 5-HT reuptake inhibitors.The present invention therefore provides, in a first aspect, a compoundof formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

-   -   R₁ is halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy or        haloC₁₋₆alkyl;    -   m is 0, 1, 2, 3 or 4;    -   X is N or CH;    -   R₂ is halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy or        haloC₁₋₆alkyl;    -   n is 0, 1 or 2;    -   W is —CH₂—, —CH(C₁₋₆alkyl)- or —C(C₁₋₆alkyl)(C₁₋₆alkyl)-;    -   p is 0, 1, 2 or 3;    -   Y and Z together form a C₃₋₇cycloalkylene group, or Y is —CH₂—,        —CH(C₁₋₆alkyl)- or —C(C₁₋₆alkyl)(C₁₋₆alkyl) and Z is —CH₂—,        —CHOH—, —CHR₆— or —CR₆R₇— (wherein R₆ and R₇ are independently        halogen, cyano, C₁₋₆alkyl or C₁₋₆alkoxy);    -   R₃ and R₄ are independently hydrogen, C₁₋₆alkyl,        C₁₋₆alkylsulfonyl or a group having the formula (II):    -    wherein        -   r is 0, 1, 2, 3 or 4;        -   A is oxygen or sulfur;        -   B is a single bond or —NR₈— (wherein R₈ is hydrogen,            C₁₋₆alkyl or aryl, wherein the aryl is optionally            substituted by one or more substituents independently            selected from halogen, oxo, C₁₋₆alkyl, CF₃, cyano, hydroxy,            C₁₋₆alkanoyl, and C₁₋₆alkoxy);        -   D is —(CH₂)_(t)—, —(CH₂)_(t)O— or —O(CH₂)_(t)—, wherein t is            0, 1, 2, 3 or 4; and        -   E is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl (optionally            substituted by one or more substituents independently            selected from halogen, hydroxy, oxo, C₁₋₆alkyl, cyano, CF₃,            OCF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl), aryl (optionally            substituted by one or more substituents independently            selected from halogen, oxo, C₁₋₆alkyl, CF₃, cyano, hydroxy,            C₁₋₆alkanoyl and C₁₋₆alkoxy), or E is —NR₉R₁₀, wherein R₉            and R₁₀ are independently selected from hydrogen, C₁₋₆alkyl            and aryl (optionally substituted by one or more substituents            independently selected from halogen, oxo, C₁₋₆alkyl, CF₃,            cyano, hydroxy, C₁₋₆alkanoyl and C₁₋₆alkoxy);    -   or R₃ and R₄, together with the nitrogen atom to which R₃ and R₄        are attached, form a 3-7 membered monocyclic heterocyclic group        or a 8-11 membered bicyclic heterocyclic group, wherein each        group is optionally substituted by one or more substituents        selected from halogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy,        C₁₋₆alkanoyl, aryl and arylC₁₋₆alkyl (wherein the aryl and the        arylC₁₋₆alkyl are further optionally substituted by one or more        halogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy or        C₁₋₆alkanoyl); and    -   R₅ is independently halogen, cyano, C₁₋₆alkyl or C₁₋₆alkoxy; and    -   q is 0, 1, 2, 3 or 4.

The term “halogen” and its abbreviation “halo” refer to fluorine,chlorine, bromine or iodine.

The term “C₁₋₆alkyl” refers to an alkyl group having from one to fourcarbon atoms, in any isomeric form, such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl,sec-pentyl, n-pentyl, isopentyl, tert-pentyl and hexyl.

The terms “haloC₁₋₆alkoxy” or “haloC₁₋₆alkyl” are used to describe aC₁₋₆alkoxy or a C₁₋₆alkyl group, respectively, substituted with one ormore halogens. Examples include —CHCl₂, —CF₃, —OCF₃, etc.

The term “C₁₋₆alkylsulfonyl” refers to a group (C₁₋₆alkyl)—SO₂—.Examples include methylsulfonyl, ethylsulfonyl and propylsulfonyl.

The term “C₃₋₇cycloalkyl” refers to a cycloalkyl group consisting offrom 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

The term “C₁₋₆alkoxy” refers to a straight chain or branched chainalkoxy (or “alkyloxy”) group having from one to six carbon atoms, suchas methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentoxy, neopentoxy, sec-pentoxy, n-pentoxy, isopentoxy,tert-pentoxy and hexoxy.

The term “C₁₋₆alkanoyl” refers to an alkanoyl group having from 1 to 6carbon atoms, such as methanoyl (or “formyl”), ethanoyl (or “acetyl”),propanoyl, isopropanoyl, butanoyl, isobutanoyl, sec-butanoyl, pentanoyl,neopentanoyl, sec-pentanoyl, isopentanoyl, tertpentanoyl and hexanoyl.

The term “aryl”, whether alone or as part of another group, is intended,unless otherwise stated, to denote, a 3- to 7-membered monocyclicaromatic ring or a 6- to 10-membered bicyclic aromatic ring, wherein oneor more of the carbon atoms in the ring(s) is optionally replaced by aheteroatom independently selected from nitrogen, oxygen and sulfur.Examples of monocyclic aryl groups include: phenyl, pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyrazolinyl, isothiazolyl, thiazolyl,isoxazolyl, furazanyl, furyl, thienyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, azepinyl and pyranyl. As used herein, the term“bicyclic aromatic ring” includes bicyclic ring systems in which bothrings are aromatic, as well as bicyclic ring systems in which one of therings is partially or fully saturated. Examples of bicyclic aryl groupsinclude: naphthyl, indenyl, indolyl, isoindolyl, indazolyl,benzimidazolyl, benzoxazolyl, benzothienyl, benzuforanyl,dihydrobenzofuranyl, tetrahydrobenzofuranyl, quinolyl, quinoxalinyl,quinazolinyl, isoquinolyl, indazylyl, indanyl, tetrahydronaphthyl,indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl,benzosazinyl, benzoxazinyl and benzoazepinyl. The term “aryl” as usedherein covers all these groups. These groups may be attached to the restof the molecule at any suitable position. For example, where used hereinthe term naphthyl, whether alone or as part of another group, isintended, unless otherwise stated, to denote both 1-naphthyl and2-naphthyl groups.

The term “oxo” refers to the group “═O”.

The term “3-7 membered monocyclic heterocyclic group” refers to a 3-7membered, saturated, partially saturated or non-saturated ringcontaining 1, 2 or 3 heteroatoms selected from nitrogen, sulfur andoxygen. The term “8-11 membered bicyclic heterocyclic group” refers toan optionally substituted 8-11 membered bicyclic ring containing a totalof 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, sulfur andoxygen, wherein each ring may be saturated, partially saturated ornon-saturated. These groups may be attached to the rest of the moleculeat any suitable position. It is understood that, when R₃ and R₄,together with the nitrogen atom to which R₃ and R₄ are attached, form anoptionally substituted 3-7 membered monocyclic heterocyclic group or anoptionally substituted 8-11 membered bicyclic heterocyclic group, theheterocyclic groups are N-linked heterocyclic groups. Examples ofN-linked 3-7 membered heterocyclic group include aziridinyl, azetidinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl,thiazolidinyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, piperidyl, piperazinyl, morpholinyl, thiazinanyl,azepinyl and azepanyl. Examples of N-linked 8-11 membered heterocyclicgroup include 6H-thieno[2,3-b]pyrrolyl, imidazo[2,1-b][1,3]thiazolyl,imidazo[5,1-b][1,3]thiazolyl, indolyl, isoindolyl, indazolyl,benzimidazolyl, decahydroquinolinyl, octahydro-2H-1,4-benzoxazinyl,octahydro-1H-cyclopenta[b]pyridinyl, indolinyl, isoindolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, benzoxazinyl,2,3-dihydro-1,4-benzoxazinyl and benzoazepinyl.

All of these heterocyclic groups formed by R₃ and R₄ may be substitutedby one or more, for example 1 to 4, substituents, which may be the sameor different, and which are selected from halogen, oxo, C₁₋₆alkyl,cyano, CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryl and arylC₁₋₆alkyl (whereinthe aryl and the arylC₁₋₆alkyl are further optionally substituted byhalogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy or C₁₋₆alkanoyl). Theoptional substituent(s) may be attached at any suitable position,including, where available, nitrogen atom(s).

It should be understood that R₁ may be attached to any availableposition in the quinoline or quinazoline group in formula (I). Forexample, it may be attached to the X if X is CH.

In one embodiment, m is 1 and R₁ is attached at the following position:

In one embodiment, n is 0. In another embodiment, n is 1 and R₂ isC₁₋₆alkyl such as methyl.

In one embodiment, p is 0.

In one embodiment, Y and Z form a C₃₋₇cycloalkylene, to form compoundssuch as:

wherein G is a C₃₋₇cycloalkylene group, such as for examplecyclopropylene.

In another embodiment, Y and Z are independently —CH₂—, —CH(CH₃)— or—CH(OH)—.

Each of R₃ and R₄ may independently be a group having the formula (II):

as defined above.

In one embodiment, formula (II) may be:

wherein A is oxygen or sulfur, D is —(CH₂)_(t)—, —(CH₂)_(t)O— or—O(CH₂)_(t)—, wherein t is 0, 1, 2, 3 or 4 and E is C₁₋₆alkyl,C₃₋₇cycloalkyl (optionally substituted by one or more substituentsindependently selected from halogen, hydroxy, oxo, C₁₋₆alkyl, cyano,CF₃, OCF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl), or aryl (optionally substitutedby one or more substituents independently selected from halogen,C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy);or

wherein A is oxygen or sulfur, D is —(CH₂)_(t)—, —(CH₂)_(t)O— or—O(CH₂)_(t)—, wherein t is 0, 1, 2, 3 or 4 and E is C₁₋₆alkyl,C₃₋₇cycloalkyl (optionally substituted by one or more substituentsindependently selected from halogen, hydroxy, oxo, C₁₋₆alkyl, cyano,CF₃, OCF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl), or aryl (optionally substitutedby one or more substituents independently selected from halogen,C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy).

When E is an optionally substituted aryl, it may for example be a 5- to7-membered monocyclic aromatic ring wherein one or more, for example 1to 4, of the carbon atoms in the ring is optionally replaced by aheteroatom independently selected from nitrogen, oxygen and sulfur (suchas for example phenyl or pyridyl), wherein the ring is optionallysubstituted by one or more substituents independently selected from oxo,halogen, C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy;or E may be for example a 9- to 10-membered bicyclic aromatic ring,wherein one or more, for example 1 to 4, of the carbon atoms in the ringis optionally replaced by a heteroatom independently selected fromnitrogen, oxygen and sulfur (such as for example tetrahydrobenzofuranyl,benzoxazolyl, benzisoxazolyl or indolinyl), wherein the ring isoptionally substituted by one or more substituents independentlyselected from oxo, halogen, C₁₋₆alkyl, CF₃, cyano, hydroxy,C₁₋₆alkanoyl, and C₁₋₆alkoxy.

Examples of E Include:

-   -   C₁₋₆alkyl such as methyl, ethyl, propyl, isopropyl, butyl,        sec-butyl or tert-butyl;    -   C₃₋₇cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and        cyclohexyl;    -   phenyl (optionally substituted by 1, 2 or 3 substituents        independently selected from CF₃, cyano, C₁₋₆alkoxy, C₁₋₆alkyl        and halogen);    -   3-7 membered monocyclic aromatic rings such as:    -    wherein w is 0, 1, 2, 3 or 4 and R is oxo, halogen, C₁₋₆alkyl,        CF₃, cyano, hydroxy, C₁₋₆alkanoyl or C₁₋₆alkoxy, wherein R may        be attached to any available atom, including any available        nitrogen atoms; and    -   6-10 membered bicyclic aromatic rings such as:    -    wherein w is 0, 1, 2, 3 or 4 and R is independently oxo,        halogen, C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl or        C₁₋₆alkoxy, wherein R may be attached to any available atom,        including any available nitrogen atoms.

When E is —NR₉R₁₀ (wherein R₉ and R₁₀ are independently selected fromhydrogen, C₁₋₆alkyl and aryl), examples of E include methylamino,ethylamino propylamino, isopropylamino, butylamino, isobutylamino,sec-butylamino, tert-butylamino, pentylamino, neopentylamino,sec-pentylamino, n-pentylamino, isopentylamino, tert-pentylamino,hexylamino; dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino, diisobutylamino, disec-butylamino,ditert-butylamino, dipentylamino, dineopentylamino, dihexylamino,butylmethylamino, isopropylmethylamino, ethylisopropylamino,ethylmethylamino; a monoarylamino such as anilino; and amonoC₁₋₆alkyl-monoarylamino such as —N(CH₃)phenyl.

When R₃ and R₄, together with the nitrogen atom to which R₃ and R₄ areattached, form an optionally substituted 3-7 membered monocyclichetercyclic group, it may be for example a 4-6 membered monocyclicheterocyclic group optionally substituted by one or more, for example 1,2, 3 or 4, substituents selected from oxo, halogen, C₁₋₆alkyl, cyano,CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryl and arylC₁₋₆alkyl (wherein the aryland the arylC₁₋₆alkyl are further optionally substituted by one or morehalogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy or C₁₋₆alkanoyl).Examples include:

wherein w is 0, 1, 2, 3 or 4 and R is independently halogen, oxo,C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryl or arylC₁₋₆alkylwherein the aryl and the arylC₁₋₆alkyl are further optionallysubstituted by one or more, for example 1 to 3, substituents selectedfrom halogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl.Examples of R include halogen such as fluoro or chloro; C₁₋₆alkyl suchas methyl, ethyl, propyl and/or isopropyl; C₁₋₆alkoxy such as methoxy orethoxy; aryl such as phenyl or pyridyl, each of which is optionallysubstituted by one or two C₁₋₆alkyl groups such as methyl, ethyl, propylor isopropyl; and arylC₁₋₆alkyl such as pyridylmethyl, optionallysubstituted by one or two C₁₋₆alkyl groups such as methyl, ethyl, propylor isopropyl. R may be attached to any available atom in the abovegroups, including any available nitrogen atoms.

When R₃ and R₄, together with the nitrogen atom to which R₃ and R₄ areattached, form an optionally substituted 8-11 membered bicyclicheterocyclic group, it may be for example a 8-10 membered bicyclicheterocyclic group optionally substituted by one or more, for example 1,2, 3, 4 or 5, substituents selected from oxo, halogen, C₁₋₆alkyl, cyano,CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryl and arylC₁₋₆alkyl (wherein the aryland the arylC₁₋₆alkyl are further optionally substituted by one or morehalogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy or C₁₋₆alkanoyl).Examples include:

wherein w is 0, 1, 2, 3 or 4 and R is independently halogen, oxo,C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryl or arylC₁₋₆alkyl,wherein the aryl and the arylC₁₋₆alkyl are further optionallysubstituted by one or more halogen, oxo, C₁₋₆alkyl, cyano, CF₃,C₁₋₆alkoxy or C₁₋₆alkanoyl. Examples of R include halogen such as fluoroor chloro, C₁₋₆alkyl such as methyl, ethyl, propyl and/or isopropyl;C₁₋₆alkoxy such as methoxy or ethoxy; aryl such as phenyl or pyridyl,each of which is optionally substituted by one or two C₁₋₆alkyl groupssuch as methyl, ethyl, propyl or isopropyl; and arylC₁₋₆alkyl such aspyridylmethyl, optionally substituted by one or two C₁₋₆alkyl groupssuch as methyl, ethyl, propyl or isopropyl. It should be noted that Rmay be attached to any available atom in the above groups, including anyavailable nitrogen atoms.

In one embodiment, q may be 0. In other embodiment, q is 1 and R₅ ishalogen such as fluoro, attached to the phenyl ring in formula (I) atthe position which is para to the group —NR₃R₄.

In one embodiment, compounds of the present invention may have a generalformula (Ia):

wherein:

-   -   R₁ is halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy or        haloC₁₋₆alkyl;    -   m is 0, 1, 2, 3 or 4;    -   X is N or CH;    -   p is 1, 2, 3 or 4;    -   Y is —CH₂—, —CH(C₁₋₆alkyl)- or —C(C₁₋₆alkyl)(C₁₋₆alkyl)-;    -   Z is —CH₂—, —CHOH—, —CHR₆— or —CR₆R₇— wherein R₆ and R₇ are        independently halogen, cyano, C₁₋₆alkyl or C₁₋₆alkoxy;    -   R₃ and R₄ are independently hydrogen, C₁₋₆alkyl,        C₁₋₆alkylsulfonyl or a group having the formula (II):    -    wherein:        -   r is 0, 1, 2, 3 or 4;        -   A is oxygen or sulfur;        -   B is a single bond or —NR₈— wherein R₈ is hydrogen,            C₁₋₆alkyl or aryl optionally substituted by one or more            substituents independently selected from halogen, oxo,            C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and            C₁₋₆alkoxy;        -   D is —(CH₂)_(t)—, —(CH₂)_(t)O— or —O(CH₂)_(t)—, wherein t is            0, 1, 2, 3 or 4; and        -   E is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl (optionally            substituted by one or more halogen, hydroxy, oxo, C₁₋₆alkyl,            cyano, CF₃, OCF₃, C₁₋₆alkoxy or C₁₋₆alkanoyl), or aryl            (optionally substituted by one or more substituents            independently selected from halogen, oxo, C₁₋₆alkyl, CF₃,            cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy); or E is            —NR₉R₁₀ (wherein R₉ and R₁₀ are independently selected from            hydrogen, C₁₋₆alkyl and aryl optionally substituted by one            or more substituents independently selected from halogen,            oxo, C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and            C₁₋₆alkoxy);    -   or R₃ and R₄, together with the nitrogen atom to which R₃ and R₄        are attached, combine to form a 3-7 membered monocyclic        heterocyclic group (optionally substituted by 1 to 4        substituents, which may be the same or different, and which are        selected from halogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy        and C₁₋₆alkanoyl);    -   R₅ is independently halogen, cyano, C₁₋₆alkyl or C₁₋₆alkoxy; and    -   q is 0, 1, 2, 3 or 4.

In another embodiment, compounds of the present invention may have ageneral formula (Ib):

wherein X, R₁, R₃ and R₄ are as defined for formula (I).

All features and embodiments of formula (I) apply to formula (Ia) and(Ib), mutatis mutandis.

Specific compounds of this invention include Example numbers 1-170(E1-E170) described below. For example, the present invention provides:

-   3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one;-   N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-phenylurea;-   N-[2-(methyloxy)phenyl]-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)urea;-   1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone;-   2,4-dimethyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-thiazole-5-carboxamide;-   N-(3-{1-hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;-   2-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide;-   3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-one;-   3-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one;-   1-methyl-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone;-   1-(4-fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone;-   3-(4-fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one;-   1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-imidazolidinedione;-   1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-one;-   1-methyl-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-one;-   4,4-dimethyl-1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone;    and pharmaceutically acceptable salts thereof.

The compounds of formula (I) can form acid addition salts thereof. Itwill be appreciated that for use in medicine the salts of the compoundsof formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric, hydroiodic, metaphosphoric,or phosphoric acid; and organic acids e.g. succinic, maleic, acetic,fumaric, citric, tartaric, benzoic, trifluoroacetic, malic, lactic,formic, propionic, glycolic, gluconic, camphorsulfuric, isothionic,mucic, gentisic, isonicotinic, saccharic, glucuronic, furoic, glutamic,ascorbic, anthranilic, salicylic, phenylacetic, mandelic, embonic(pamoic), ethanesulfonic, pantothenic, stearic, sulfinilic, alginic andgalacturonic acid; and arylsulfonic, for example benzenesulfonic,p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid; baseaddition salts formed with alkali metals and alkaline earth metals andorganic bases such as N,N-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine),lysine and procaine; and internally formed salts. Certain of thecompounds of formula (I) may form acid addition salts with less than oneor one or more equivalents of the acid, for example to form adihydrochloride salt. The present invention includes within its scopeall possible stoichiometric and non-stoichiometric forms. Salts having anon-physiologically acceptable anion or cation are within the scope ofthe invention as useful intermediates for the preparation ofphysiologically acceptable salts and/or for use in non-therapeutic, forexample, in vitro, situations.

The compounds of formula (I) may be prepared in crystalline ornon-crystalline form, and, if crystalline, may optionally be hydrated orsolvated. This invention includes within its scope stoichiometrichydrates or solvates as well as compounds containing variable amounts ofwater and/or solvent.

Certain compounds of formula (I) are capable of existing instereoisomeric forms (e.g. geometric (or “cis-trans”) isomers,diastereomers and enantiomers) and the invention extends to each ofthese stereoisomeric forms and to mixtures thereof including racemates.The different stereoisomeric forms may be separated one from the otherby the usual methods, or any given isomer may be obtained bystereospecific or asymmetric synthesis. The invention also extends toany tautomeric forms and mixtures thereof. The present inventionincludes within its scope all such isomers, including mixtures.

Compounds of formula (I) may be prepared according to proceduresdescribed herein, or by analogous procedures thereto.

A reaction route for a compound of formula (I) wherein m is 1 and R₁ ismethyl, p is 0, n is 0, and q is 0, is as follows:

The above reaction scheme may be adapted to prepare compounds of formula(I) wherein m is other than 1, R₁ is other than methyl and in a positionother than as illustrated above, and p, n and q are other than 0.

Compounds of formula (I) wherein Y and Z together form aC₃₋₇cycloalkylene group may be prepared according to proceduresdescribed herein, or by analogous procedures thereto.

A typical reaction route for a compound of formula (I) wherein Y and Ztogether form a cyclopropylene group, and wherein m is 1 and R₁ ismethyl, p is 0, n is 0, and q is 0, is as follows:

wherein X, R₃ and R₄ are as defined for formula (I). Thus, treatment ofthe piperazine described above with a 2-arylacetaldehyde produces anenamine, which can be treated under reaction conditions known to thoseskilled in the art, e.g. Simmons-Smith cyclopropanation reaction usingdiiodoethane and diethylzinc, to produce compounds of formula (I)wherein Y and Z together form a C₃₋₇cycloalkylene group. The abovereaction scheme may be adapted to prepare compounds of formula (I)wherein m is other than 1, R₁ is other than methyl and in a positionother than as illustrated above, p, n and q are other than 0, and Y andZ form a C₃₋₇cycloalkylene group other than cyclopropylene.

Alternatively, the reaction of an aromatic nucleophile such as aGrignard reagent (M=MgX) or aryllithium (M=Li) with a cycloalkyl epoxide(where n=0,1,2), optionally in the presence of a catalyst e.g. acopper(l) halide, may provide an intermediate alcohol, as illustrated inthe scheme below. The alcohol may conveniently be converted into aketone using a suitable oxidising agent, e.g. pyridinium chlorochromate.The ketone may then be transformed to a compound of formula (I) usingmethods described in the preceding scheme.

The above scheme illustrates the case where p is 0, but may be adaptedfor cases where p is other than 0.

Alternatively, the reaction of an aromatic nucleophile such as aGrignard reagent (M=MgX) or aryllithium (M=Li) with an α, β-unsaturatedketone (where n=1,2), in the presence of a catalyst e.g. a copper(I)halide may provide a cycloalkyl ketone product. The ketone may then betransformed to a compound of formula (I) using methods described above.

The above scheme illustrates the case where p is 0, but may be adaptedfor cases where p is other than 0.

Alternatively, the treatment of a substituted 2-phenyl acetyl chloridewith diazomethane may produce a regioisomeric mixture of the 1,2 and1,3-cyclobutyl ketone derivatives (Synthesis, 1977, (6), 411). Theketone regioisomers may then be transformed to a compound of formula (I)using methods described above.

The above scheme illustrates the case where p is 0, but may be adaptedfor cases where p is other than 0.

Compounds of formula (I) can also be prepared according to the schemebelow. Reaction of a substituted benzaldehyde with a reagent such asmethoxymethyltriphenylphosphonium chloride in the presence of a suitablebase, e.g. potassium carbonate or sodium methoxide or sodium hydride,produces an enol ether. The enol ether can be hydrolysed under acidicconditions, e.g. using aqueous hydrochloric acid optionally in asuitable co-solvent such as tetrahydrofuran, to give a substituted2-phenylacetaldehyde derivative. The aldehyde can be reductively coupledto a 5-(1-piperazinyl)quinoline or quinazoline compound using conditionsfamiliar to those skilled in the art e.g. using sodiumtriacetoxyborohydride or sodium cyanoborohydride. The product may beconverted to a compound of formula (I) using methods describedpreviously (if the aromatic substituents do not already include a groupof formula —NR₃R₄).

The above scheme illustrates the case where p is 0, but may be adaptedfor cases where p is other than 0.

Alternatively, compounds of formula (I) may be prepared according to thefollowing scheme. Esterification of a 3-aminophenylacetic acidderivative under acidic conditions in an alcoholic solvent e.g.trimethylsilyl chloride in methanol produces the acetate esterhydrochloride. Reaction of the ester hydrochloride with a reagent suchas a 2-halo-ethyl-isocyanate or a synthetic equivalent thereof, e.g.sequential addition of phosgene (or equivalent e.g. carbonyldiimidazole,disuccinimidyl carbonate) and a 2-haloethylamine (Y═NH₂) or2-haloethanol (Y═OH), optionally in the presence of a base, produces anintermediate where X is a leaving group as defined previously. Treatmentof the intermediate with a strong base, such as sodium hydride, producesa cyclised product. Reduction of the ester group with a suitablereagent, for example lithium borohydride, produces a substituted3-phenyl ethanol derivative. Conversion of the alcohol group to asulfonate leaving group, such as by reaction with a sulfonic anhydrideor sulfonyl chloride e.g. methanesulfonyl chloride, optionally in thepresence of a suitable base, produces a compound, which can be convertedto a compound of formula (I) according to the procedures describedpreviously.

Thus, in a further aspect, this invention provides a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which process comprises the steps of:

(a) converting a compound of formula (III):

wherein R₁, m, X, R₂, n, W, p, Y, Z, R₅ and q are as defined for formula(I), or

(b) for a compound of formula (I) wherein Y and Z form a cyclopropylenegroup, converting a compound of formula (IV):

wherein R₁, m, X, R₂, n, W, p, R₃, R₄ and R₅ and q are as defined forformula (I); or

(c) reacting a compound of formula (V):

wherein R₁, m, X, R₂, n, W, p, Y, Z, R₅ and q are as defined for formula(I), and L is a leaving group, with a compound of formula (VI):R₃R₄NH  (VI)wherein R₃ and R₄ are as defined for formula (I); or

(d) reacting a compound of formula (VII):

wherein R₁, m, X, R₂ and n are as defined for formula (I), with acompound of formula (VIII):

wherein W, p, Y, Z, R₅, q, R₃ and R₄ are as defined for formula (I), andL is a leaving group; or

(e) for a compound of formula (I) wherein Z is —CH(OH), reacting acompound of

formula (VII) as defined in step (d) with a compound of formula (XIII):wherein W, p, Y, Z, R₅, q R₃ and R₄ are as defined for formula (I);or

(f) for a compound of formula (I) wherein Y and Z form aC₃₋₇cycloalkylene group, reacting a compound of formula (VII) as definedabove with a compound of formula (XIV):

wherein R₅, R₂, R₃ and q are as defined for formula (I), a is 0, 1, 2, 3or 4;or

(g) for a compound of formula (I) wherein the group W or Y attached tothe nitrogen in the piperazine group in formula (I) is CH₂ orCH(C₁₋₆alkyl), reacting a compound of formula (VII) as defined abovewith a compound of formula (XV):

wherein R₃, R₄, R₅ q Z Y and W are as defined for formula (I), b is 0, 1or 2 and Q is hydrogen or C₁₋₆alkyl;and thereafter optionally for any of steps (a) to (g):

-   -   removing any protecting groups and/or    -   converting a compound of formula (I) into another compound of        formula (I) and/or    -   forming a pharmaceutically acceptable salt.

In step (a), a compound of formula (III) is converted to form a compoundof formula (I) by standard reduction reactions known to the skilledperson, for example by reaction with iron and NH₄OH to form a compoundof formula (I) wherein R₃ and R₄ are both hydrogen. Such compounds maythen be converted to other compounds of formula (I) as described below.Compounds of formula (III) may be prepared according to proceduresdescribed herein, by known literature methods, or by analogousprocedures thereto.

A compound of formula (I) wherein Y and Z form a cyclopropylene groupmay be made by step (b), by conversion of a compound of formula (IV). Asnoted above, the conversion reaction may be for example a Simmons-Smithreaction. Compounds of formula (IV) may be prepared according toprocedures described herein, by known literature methods, or byanalogous procedures thereto. For example, compounds of formula (IV) maybe made by reacting a compound of formula (VII) as defined above with acompound of formula (XVI):

wherein p, W, R₃, R₄, R₅ and q are as defined for formula (I).

In step (c), a compound of formula (V) is reacted with a compound offormula (VI). The reaction may take place under conditions known tothose skilled in the art, for example optionally in the presence of acopper-based catalyst. Compounds of formula (V) may be preparedaccording to procedures described herein, by known literature methods,or by analogous procedures thereto.

In step (d), a compound of formula (VII) is reacted with a compound offormula (VIII). Suitable reaction conditions for step (d) include theuse of a base, for example triethylamine or N′N-diisopropylethylamine,in a suitable solvent such as dimethylformamide, acetonitrile,dimethylsulfoxide or N-methylpyrrolidinone with optional heating of thereaction to a temperature between 30 and 200° C., preferably between 50and 150° C.

Suitable leaving groups for aliphatic nucleophilic substitution (J.March, Advanced Organic Chemistry, 4^(th) Edition, John Wiley and Sons,1992, pp. 351-356) include, but are not limited to: halides e.g. chloro,bromo, iodo; sulfate; sulfonate esters e.g. tosylate, brosylate,nosylate and mesylate; dialkylphosphates; oxonium ions; perchlorates,betylates (ammonioalkanesulfonate esters); activated sulfonate esterse.g. fluorosulfonate, triflate, nonaflate and tresylate; halonium ions;ditosylamine; and 1-pyridinium salts.

Suitable leaving groups for aromatic substitution (J. March, AdvancedOrganic Chemistry, 4^(th) Edition, John Wiley and Sons, 1992, pp.652-653) include, but are not limited to: halides e.g. fluoro, chloro,bromo, iodo; trialkylammonium; diazo; sulfate; sulfonate esters e.g.tosylate, brosylate, nosylate and mesylate phenylsulfanyl,phenylsulfonyl; activated sulfonate esters e.g. fluorosulfonate,triflate, nonaflate and tresylate; phosphate; dialkyl phosphate; nitro;alkoxy; aryloxy; alkylsulfonyl; and alkylsulfanyl.

Compounds of formula (VIII) may be prepared for example by converting acompound of formula (XVII):

wherein W, p, Y, Z, R₃, R₄, R₅ and q are as defined for formula (I), tointroduce the leaving group L by for example reacting with MeSO₂Cl.

The present invention provides a process for the preparation of acompound of formula (la) as defined above or a pharmaceuticallyacceptable salt thereof, which process comprises the step of reacting acompound of formula (XVIII):

wherein R₁, m, X, Y, p, Z, R₅ and q are as defined for formula (Ia)above, with compound(s) containing appropriate functional group(s) whichis/are capable of reacting with a compound of formula (XVIII) to form acompound of formula (I). Compounds of formula (XVIII) may be preparedaccording to procedures described herein, by known literature methods,or by analogous procedures thereto.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard techniques. For example, and by way ofillustration rather than limitation, possible conversion reactionsinclude acylation with an appropriate acylating agent such as acetylchloride, alkylation using an appropriate alkylating reagent such asmethyl iodide, and sulfonylation using a sulfonylating agent such asmethanesulfonic anhydride. For example, for a compound of formula (I)wherein R₃ and R₄ are independently C₁₋₆alkylsulfonyl, a compound offormula (I) wherein R₃ and R₄ are both hydrogen may be reacted with aC₁₋₆alkylsulfonylchloride. For a compound of formula (I) wherein R₃ andR₄ are independently formula (II), a compound of formula (I) wherein R₃and R₄ are both hydrogen may be reacted with a compound of formula(XIX):

wherein r, A, B, D and E are as defined for formula (II) above, and Q isa suitable leaving group such as chlorine, or is —OH when r is zero. Toobtain a compound of formula (I) wherein B is —NR₈, an appropriateisocyanate or isothiocyanate may be used. On the other hand, forcompounds of formula (I) wherein R₃R₄, together with the nitrogen atomto which R₃ and R₄ are attached, form a 3-7 membered monocyclicheterocyclic group, an appropriate chloroformate or an isocyanate may beused to react with a compound of formula (I) wherein R₃ and R₄ are bothhydrogen.

It will be appreciated by those skilled in the art that it may benecessary to protect certain reactive substituents during some of theabove procedures. Standard protection and deprotection techniques, suchas those described in Greene T. W. Protective groups in organicsynthesis, New York, Wiley (1981), can be used. For example, primaryamines can be protected as phthalimide, benzyl, t-butyloxycarbonyl,benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can beprotected as esters. Aldehyde or ketone groups can be protected asacetals, ketals, thioacetals or thioketals. Deprotection of such groupsis achieved using conventional procedures well known in the art. Forexample, protecting groups such as t-butyloxycarbonyl may be removedusing an acid such as hydrochloric or trifluroroacetic acid in asuitable solvent such as dichloromethane, diethylether, isopropanol ormixtures thereof.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

The affinities of the compounds of this invention for 5-HT_(1A),5-HT_(1B) and 5-HT_(1D) receptors can be determined by the followingassay. CHO cells expressing 5-HT_(1A) receptors (4×10⁷ cells/ml) arehomogenised in Tris buffer and stored in 1 ml aliquots. CHO cellsexpressing 5-HT_(1B) receptors (4×10⁷ cells/ml) are homogenised in Trisbuffer and stored in 1.5 ml aliquots. CHO cells expressing 5-HT_(1D)receptors (1×10⁸/ml) are homogenised in Tris buffer and stored in 1 mlaliquots. 0.4 ml of a cell suspension is incubated with [³H]-5-HT (4 nM)for 5-HT_(1B/1D) receptors and [³H]WAY100635 (1 nM) for 5-HT_(1A)receptors in Tris Mg HCl buffer (pH 7.7) and test drug, at 37° C. for 45minutes. Each test drug is tested at 10 concentrations (0.01 mM to 0.3nM final concentration), with non-specific binding defined using 0.01 mM5-HT. The total assay volume is 0.5 ml. Incubation is stopped by rapidfiltration using a Packard Filtermate and radioactivity measured byTopcount scintillation counting. pKi values are calculated from the IC₅₀generated by an iterative least squares curve fitting programme.

Alternatively, functional potency can be measured by the following GTPγSbinding protocol. Cells used in the study are Chinese Hamster Ovary(CHO) Cells, Human Embryo Kidney (HEK293). Cells were transfected withDNA coding for human receptors.

-   Cell Line-   HEK293_(—)5-HT1A-   CHO_(—)5-HT1B-   CHO_(—)5-HT1D

Compounds were initially dissolved in 100% Dimethyl Sulphoxide at aconcentration of 10 mM. Serial dilution of drugs in 100% DimethylSulphoxide were carried out using a Biomek FX. The final topconcentration of compound was 3 uM in the assay. The compound at 1.0%total assay volume (TAV) was added to a solid, white, 384 well assayplate (Costar). 50% TAV of precoupled (for 90 mins @ RT) membranes, 5ug/well, and Wheatgerm Agglutinin Polystyrene Scintillation ProximityAssay beads (RPNQO260 Amersham International), 0.25 mg/well, in 20 mMHEPES pH 7.4, 100 mM NaCl, 3 mM MgCl₂ and 10 μM GDP was added. The thirdaddition was a 20% TAV addition of either buffer, agonist format, orEC₈₀ final assay concentration (FAC) of agonist, 5HT antagonist format,prepared in assay buffer. The assay was started by the addition of 29%TAV of GTP□S 0.38 nM FAC. After all additions assay plates wereincubated at RT for 2-3 hours. Assay plates were counted on a Viewlux,613/55 filter for 5 mins. Assay plates were read between 2-6 hours afterthe final addition.

The Example compounds shown below were tested and were found to have pKivalues >6.0 at 5-HT_(1A) receptors, with many showing a considerablyhigher affinity (having pKi values in the range 8.0-10.0) Certaincompounds of this invention also demonstrate comparable affinity for5-HT_(1B) and 5-HT_(1D) receptors.

The intrinsic activity of the compounds of this invention can bedetermined according to the following assay. HEK293 cell membranesstably expressing human 5-HT_(1A) receptors and CHO cell membranesstably expressing human 5-HT_(1B) receptors are homogenised inHEPES/EDTA buffer and stored in 1 ml aliquots, and [³⁵S]GTPγS bindingstudies are carried out essentially as described by Lazareno et al.,(Life Sci., 1993, 52, 449) with some minor modifications. Membranes from10⁶ cells are pre-incubated at 30° C. for 30 minutes in 20 mM HEPESbuffer (pH 7.4) in the presence of MgCl₂ (3 mM), NaCl (100 mM), GDP (10μM) and ascorbate (0.2 mM), with or without test compounds. The reactionis started by the addition of 50 μl of [³⁵S]GTPγS (100 pM, assayconcentration) followed by a further 30 minutes incubation at 30° C.Non-specific binding is determined using nonradiolabelled GTPγS (20 μM)added prior to the membranes. The reaction is terminated by rapidfiltration through Whatman GF/B grade filters followed by 5×1 ml washeswith ice cold HEPES (20 mM)/MgCl₂ (3 mM) buffer. Radioactivity ismeasured using liquid scintillation spectrometry. This procedure ishereafter referred to as the [³⁵S]GTPγS functional assay.

It has been found, using the [³⁵S]GTPγS functional assay, that certaincompounds of formula (I) appear to be antagonists at 5-HT₁ typereceptors whilst others appear to be inverse agonists, agonists orpartial agonists.

The efficacy of the compounds of this invention to inhibit the re-uptakeof serotonin can be measured in a 5-HT uptake assay by measurement ofuptake of [³H]-5-HT into LLCPK cells expressing human or rat serotonintransporters. In brief, cells are harvested and plated onto 96-wellplates (10,000 cells per well). 24 hr later cells are washed 2× withHBSSH (Hanks' balanced salt solution +20 mM HEPES). 50 ul of testcompound or vehicle is added to each well and incubated for 10 min.Subsequently, [³H]5-HT (final concentration 25 nM) is added and the testmixture is incubated for a further 7 min. The reaction is terminated byaspiration of test mixture and the cells are washed 6× with HBSSH. 50 ulof scintillation cocktail (Microscint-20, Packard) is added onto thecells and the top and bottom of the plate is sealed. Plates are read, 30min later, in a Packard TopCount.

Alternatively: the potency of the compounds to bind the re-uptake siteof serotonin may be assessed using [3H]citalopram binding assaysperformed in recombinant epithelial pig kidney cells stably transfectedwith human SERT (hSERT/LLCPK). The cells were grown onto Petri dishes of500 cm². At 80% of confluence the cells were harvested in phosphatebuffered saline (PBS) containing 5 mM EDTA and centrifuged at 900 g for8 min at 4° C. The pellet was homogenized in 30-50 vols of assay buffer(50 mM Tris, 120 mM NaCl, 5 mM KCl, 10 μM Pargyline, 0.1% Ascorbate(pH=7.7)) and centrifuged at 48000 g for 20 min at 4° C. The pellet wasresuspended in the same volume and after incubation at 37° C. for 20min, centrifuged as before and finally alquoted at ˜0.2 mg protein/ml incold assay buffer. [3H]citalopram binding assays consisted of 100 μl oftest compound, assay buffer (to define total binding) or a finalconcentration of 10 μM paroxetine (to define non-specific binding), 100μl of [3H]Citalopram at final concentration of 0.25 nM and 200 μl ofmembranes diluted in assay buffer at concentration of 2 μg/well ofprotein. Membranes were added last to initiate the reaction andincubated at room temperature for 2 h. The reaction was then stopped byrapid filtration through GF/B 96-filterplate pre-soaked in 0.5%polyethylenimmine (PEI) using a Packard cell harvester. 96-filterplatewas washed 3 times with 1 ml/well cold 0.9% NaCl solution and theradioactivity was counted in Packard TopCount.

Some of the Example compounds tested according to this uptake assay werefound to have potency at the uptake site of pIC₅₀ of >6.0.

Compounds of formula (I) and their pharmaceutically acceptable salts areof use in the treatment of certain CNS disorders such as depression(which term includes bipolar depression, unipolar depression, single orrecurrent major depressive episodes with or without psychotic features,catatonic features, melancholic features, atypical features orpostpartum onset, seasonal affective disorder and dysthymia, depressivedisorders resulting from a general medical condition including, but notlimited to, myocardial infarction, diabetes, miscarriage or abortion),anxiety disorders (which includes generalised anxiety and social anxietydisorder), schizophrenia, panic disorder, agoraphobia, social phobia,obsessive compulsive disorder, post-traumatic stress disorder, pain(particularly neuropathic pain), memory disorders (including dementia,amnesic disorders and age-associated memory impairment), disorders ofeating behaviours (including anorexia nervosa and bulimia nervosa),sexual dysfunction, sleep disorders (including disturbances of circadianrhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawalfrom abuse of drugs (such as of cocaine, ethanol, nicotine,benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-likecompounds, opiates such as cannabis, heroin, morphine, sedative ipnotic,amphetamine or amphetamine-related drugs such as dextroamphetamine,methylamphetamine or a combination thereof), motor disorders such asParkinson's disease, dementia in Parkinson's disease,neuroleptic-induced Parkinsonism and tardive dyskinesias, as well asother psychiatric disorders, and certain gastrointestinal disorders suchas irritable bowel syndrome. The compounds may also be useful intreating tumours such as prostate tumours.

It is to be understood that “treatment” as used herein includesprophylaxis as well as alleviation of established symptoms.

Thus the invention also provides a compound of formula (I) or apharmaceutically acceptable salt thereof, for use as a therapeuticsubstance, in particular in the treatment of a CNS disorder such asdepression (which term includes bipolar depression, unipolar depression,single or recurrent major depressive episodes with or without psychoticfeatures, catatonic features, melancholic features, atypical features orpostpartum onset, seasonal affective disorder and dysthymia, depressivedisorders resulting from a general medical condition including, but notlimited to, myocardial infarction, diabetes, miscarriage or abortion),anxiety disorders (which includes generalised anxiety and social anxietydisorder), schizophrenia, panic disorder, agoraphobia, social phobia,obsessive compulsive disorder, post-traumatic stress disorder, pain(particularly neuropathic pain), memory disorders (including dementia,amnesic disorders and age-associated memory impairment), disorders ofeating behaviours (including anorexia nervosa and bulimia nervosa),sexual dysfunction, sleep disorders (including disturbances of circadianrhythm, dyssomnia, insomnia, sleep apnea and narcolepsy), withdrawalfrom abuse of drugs (such as of cocaine, ethanol, nicotine,benzodiazepines, alcohol, caffeine, phencyclidine and phencyclidine-likecompounds, opiates such as cannabis, heroin, morphine, sedative ipnotic,amphetamine or amphetamine-related drugs such as dextroamphetamine,methylamphetamine or a combination thereof), motor disorders such asParkinson's disease, dementia in Parkinson's disease,neuroleptic-induced Parkinsonism and tardive dyskinesias, as well asother psychiatric disorders, and certain gastrointestinal disorders suchas irritable bowel syndrome, and tumours such as prostate tumours.

In particular the invention provides a compound of formula (I) or apharmaceutically acceptable salt thereof for use as a therapeuticsubstance in the treatment of depression and/or anxiety.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, serotonin agonists, NK-1antagonists, selective serotonin reuptake inhibitors (SSRI),noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressantsand/or dopaminergic antidepressants.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination orcomposition may be administered simultaneously (either in the same ordifferent pharmaceutical formulations), separately or sequentially.

The invention further provides a method of treatment of the abovedisorders in mammals including humans, which comprises administering tothe sufferer a therapeutically safe and effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides for the use of a compound offormula (I) or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for use in the treatment of the abovedisorders.

In order to use the compounds of formula (I) in therapy, they willnormally be formulated into a pharmaceutical composition in accordancewith standard pharmaceutical practice. The present invention alsoprovides a pharmaceutical composition, which comprises a compound offormula (I) or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or excipient.

In a further aspect, the present invention provides a process forpreparing a pharmaceutical composition, the process comprising mixing acompound of formula (I) or a pharmaceutically acceptable salt thereofand a pharmaceutically acceptable carrier or excipient.

A pharmaceutical composition of the invention, which may be prepared byadmixture, suitably at ambient temperature and atmospheric pressure, isusually adapted for oral, parenteral or rectal administration and, assuch, may be in the form of tablets, capsules, oral liquid preparations,powders, granules, lozenges, reconstitutable powders, injectable orinfusible solutions or suspensions or suppositories. Orallyadministrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form,and may contain conventional excipients, such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose);, fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate);, tabletting lubricants lubricants (e.g.magnesium stearate, talc or silica);, disintegrants (e.g. potato starchor sodium starch glycollate); and acceptable wetting agents (e.g. sodiumlauryl sulphate). The tablets may be coated according to methods wellknown in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspension, solutions, emulsions, syrups or elixirs, or may be inthe form of a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents (e.g. sorbitol syrup,cellulose derivatives or hydrogenated edible fats), emulsifying agents(e.g. lecithin or acacia), non-aqueous vehicles (which may includeedible oils e.g. almond oil, oily esters, ethyl alcohol or fractionatedvegetable oils), preservatives (e.g. methyl or propyl-p-hydroxybenzoatesor sorbic acid), and, if desired, conventional flavourings or colorants,buffer salts and sweetening agents as appropriate. Preparations for oraladministration may be suitably formulated to give controlled release ofthe active compound.

For parenteral administration, fluid unit dosage forms are preparedutilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle. Formulations for injection may bepresented in unit dosage form e.g. in ampoules or in multi-dose,utilising a compound of the invention or pharmaceutically acceptablesalt thereof and a sterile vehicle, optionally with an addedpreservative. The compositions may take such forms as suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilising and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use. The compound, depending on the vehicle and concentrationused, can be either suspended or dissolved in the vehicle. In preparingsolutions, the compound can be dissolved for injection and filtersterilised before filling into a suitable vial or ampoule and sealing.Advantageously, adjuvants such as a local anaesthetic, preservatives andbuffering agents are dissolved in the vehicle. To enhance the stability,the composition can be frozen after filling into the vial and the waterremoved under vacuum. Parenteral suspensions are prepared insubstantially the same manner, except that the compound is suspended inthe vehicle instead of being dissolved, and sterilisation cannot beaccomplished by filtration. The compound can be sterilised by exposureto ethylene oxide before suspension in a sterile vehicle.Advantageously, a surfactant or wetting agent is included in thecomposition to facilitate uniform distribution of the compound.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device. Thuscompounds of formula (I) may be formulated for oral, buccal, parenteral,topical (including ophthalmic and nasal), depot or rectal administrationor in a form suitable for administration by inhalation or insufflation(either through the mouth or nose).

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

The composition may contain from 0.1% to 99% by weight, preferably from10 to 60% by weight, of the active material, depending on the method ofadministration. The dose of the compound used in the treatment of theaforementioned disorders will vary in the usual way with the seriousnessof the disorders, the weight of the sufferer, and other similar factors.However, as a general guide suitable unit doses may be 0.05 to 1000 mg,more suitably 1.0 to 200 mg, and such unit doses may be administeredmore than once a day, for example two or three times a day. Such therapymay extend for a number of weeks or months.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Preparations and Examples illustrate the compounds of thepresent invention and preparation thereof.

DESCRIPTION 1 2-Methyl-5-quinolinyl trifluoromethanesulfonate (D1)

A solution of 2-methyl-quinolin-5-ol (2.5 g; 1 eq) in dichloromethane(25 mL) and pyridine (6.4 mL; 5 eq) was cooled to 0° C. andtrifluoromethanesulfonic anhydride (4.2 mL; 1.6 eq) was added dropwiseover 10 minutes. The reaction mixture was stirred under an inertatmosphere at r.t. for 1 h, then poured into water (20 mL) and extractedinto ethyl acetate (3×15 mL). The organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure. The crude waspurified by flash chromatography, eluting with ethyl acetate/cyclohexane(4/6) affording the title compound in 92% yield (4.2 g).

MS; (ES) m/z: 292.3 [MH⁺]. C₁₁H₈F₃NO₃S requires 291. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 8.05 (d, 1H), 7.85 (d, 1H), 7.64 (t, 1H), 7.48 (d, 1H),7.43 (d, 1H), 2.48 (s, 3H).

DESCRIPTION 2 1,1-Dimethylethyl4-(2-methyl-5-quinolinyl)-1-piperazinecarboxylate (D2)

tert-Butyl 1-piperazine carboxylate (1.6 g; 1.2 eq), cesium carbonate(1.7 g; 1.5 eq), palladium acetate (0.33 g; 0.14 eq) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.97 mg; 0.15 eq) wereadded to a solution of 2-methyl-5-quinolinyl trifluoromethanesulfonate(D1) in toluene (20 mL) under an inert atmosphere. The reaction mixturewas stirred at reflux under nitrogen for 8 hours. The reaction wasquenched at room temperature using a saturated aqueous solution ofammonium chloride (15 mL) and extracted into ethyl acetate (3×20 mL).The organic layers were combined, dried over Na₂SO₄ and concentratedunder reduced pressure. The crude was purified by flash chromatography,eluting with ethyl acetate/cyclohexane (3/7) affording the titlecompound in 62% yield (1.4 g).

MS; (ES) m/z: 328.4 [MH]⁺. C₁₉H₂₅N₃O₂ requires 327. ¹H-NMR (500 MHz,CDCl₃) δ(ppm): 8.40 (d, 1H), 7.76 (d, 1H), 7.61 (t, 1H), 7.29 (d, 1H),7.06 (d, 1H), 3.69 (bs, 4H), 3.03 (bs, 4H), 2.74 (s, 3H), 1.51 (s, 9H).

DESCRIPTION 3 2-Methyl-5-(1-piperazinyl)quinoline (D3)

1,1-dimethylethyl 4-(2-methyl-5-quinolinyl)-1-piperazinecarboxylate (D2)(1.1 g) in a 25% solution of trifluoroacetic acid in dichloromethane (10mL) was stirred at r.t. under an inert atmosphere for 3 hours. Thereaction mixture was concentrated under reduced pressure and desalted bymeans of a 20 g SCX cartridge affording the title compound in 96% yield(0.74 g).

MS; (ES) m/z: 228.4 [MH]⁺. C₁₄H₁₇N₃ requires 227. ¹H-NMR (300 MHz,d₆-DMSO) δ(ppm): 8.34 (d, 1H), 7.57 (m, 2H), 7.35 (m, 1H), 7.06 (m, 1H),2.93 (bm, 8H), 2.62 (s, 3H).

DESCRIPTION 4 2-(3-Nitrophenyl)ethyl methanesulfonate (D4)

Methanesulfonyl chloride (0.28 mL) was added dropwise to a stirredsolution of 2-(3-nitrophenyl)ethanol (0.5 g; 1 eq) in dichloromethane (3mL) and triethylamine (0.5 mL; 1.2 eq) at 0° C. under an inertatmosphere. The solution was allowed to reach r.t. and stirred for 5hours. The reaction mixture was diluted with water (3 mL) and extractedinto dichloromethane (3×3 mL). The organic layers were combined, driedover Na₂SO₄ and concentrated under reduced pressure. The crude waspurified by flash chromatography, eluting with a gradient fromdichloromethane to dichloromethane/MeOH (98/2) affording the titlecompound in 84% yield (0.62 g).

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 8.15 (m, 2H), 7.53 (m, 2H), 4.45 (t,2H), 3,15 (t, 2H), 2.92 (s, 3H).

DESCRIPTION 52-Methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (D5)

N,N-Diisopropylethylamine (0.8 mL; 5 eq) was added to a solution of2-methyl-5-(1-piperazinyl)quinoline (D3) (0.2 g; 1 eq) and2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.22; 1 eq) indimethylformamide (1.5 mL). The reaction mixture was heated to 100° C.for 10 hours. The dark solution was concentrated under reduced pressure,diluted with water (3 mL) and brine (1 mL) and extracted into ethylacetate (3×3 mL). The organic layers were combined, dried over Na₂SO₄and concentrated under reduced pressure. The crude was purified by flashchromatography, eluting with a gradient from dichloromethane todichloromethane/MeOH (98/2) affording the title compound in 64% yield(0.21 g).

MS; (ES) m/z: 228.4 [MH]⁺. C₂₂H₂₄N₄O₂ requires 376. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 8.11 (s, 1H), 8.05 (d, 1H), 7.70 (d, 1H),7.55 (m, 2H), 7.45 (t, 1H), 7.25 (m, 1H), 7.05 (d, 1H), 3.10 (mt, 4H),2.95 (bm, 2H), 2.75 (bm, 6H), 2.70 (s, 3H).

DESCRIPTION 63-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6)

A solution of2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline (D5)(0.14g; 1 eq) in methanol (3 mL) was added dropwise to a suspension of ironpowder (0.07 g; 3.2 eq) and ammonium chloride (0.1 g; 5.3 eq) in water(3 mL). The reactants were heated at reflux for 8 hours, addingadditional amounts of iron powder (total 0.07 g; 3.2 eq) and ammoniumchloride (total 0.1 g; 5.03 eq) in 3 portions during the reaction. Thereaction mixture was filtered using a Millipore filter. The filtrate wasconcentrated under reduced pressure, diluted with water (5 mL) and asaturated aqueous solution of sodium hydrogen carbonate (2 mL),extracted into ethyl acetate (3×5 mL), dried over Na₂SO₄ andconcentrated under reduced pressure obtaining the title compound in 84%yield (0.11 g).

MS; (ES) m/z: 347.4 [MH]⁺. C₂₂H₂₆N₄ requires 346. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.25 (d, 1H),7.08 (m, 2H), 6.65 (md, 1H), 6.55 (m, 2H), 3.65 (bs, 2H), 3.15 (t, 4H),2.80 (m, 4H), 2.75 (s, 3H), 2.70 (m, 4H).

DESCRIPTION 7N-Methyl-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D7)

Propyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)carbamatedihydrochloride (E47) (0.065 mmol) was charged onto an SPE cartridge(SCX) and eluted with a solution of ammonia in MeOH to obtain thecorresponding free base (0.0618 mmol). This was then dissolved intetrahydrofuran (1 ml) and treated with LiAlH₄ (3 equiv.). The resultingreaction mixture was warmed to 70° C. and stirred for 3 h. Then, thereaction mixture was poured into NH₄Cl aq. at 0° C. The aqueous phasewas extracted with dichloromethane (20 ml). The organic phases werewashed with water, dried over Na₂SO₄ and concentrated under reducedpressure. The crude was purified on SPE cartridge (Silica) usingCH₂Cl₂/MeOH (98/2) as eluent to give the title compound in 43% yield.

MS: (ES/+) m/z: 361 [MH⁺]. C₂₃H₂₈N₄ required 360. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (1H, d), 7.70 (1H, d), 7.65 (1H, t), 7.15-7.00 (2H,m), 6.55 (1H, d), 6.50-6.40 (2H, m) 3.15 (4H, m), 2.85-2.65 (8H, m),2.80 (3H, s), 2.70 (3H, s).

DESCRIPTION 81-(3-Aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(D8)

Sodium carbonate (1.5 eq) and 2-bromo-1-(3-nitrophenyl)ethanone (1.5 eq)were added to a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline(D3) (1 eq) in tetrahydrofuran at room temperature under an inertatmosphere, and the reaction was left under stirring for 1 h. Thesolution was then diluted with MeOH, NaBH₄ (2 eq) was added and thereaction was left under stirring for 1 h. The solvent was removed underreduced pressure.

The crude material was purified on SPE cartridge (SCX) using as eluant agradient from MeOH to MeOH:CH₂Cl₂ (1:1) and then 2M NH₃ in MeOHaffording an intermediate which was reduced following a similarprocedure to D6 to give the title compound in 55% yield.

MS: (ES/+) m/z: 363 [MH⁺]. C₂₂H₂₆N₄0 required 362. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (1H, d), 7.70 (1H, d), 7.55 (1H, t), 7.25 (1H, d),7.10 (1H, t), 7.05 (1H, d), 6.80-6.70 (2H, m), 6.60 (1H, dd), 4.70 (1H,dd), 3.65 (2H, bs), 3.15 (4H, bs), 3.00 (2H, bm), 2.80-2.50 (7H, m).

General Procedure for the Preparation of Amides, Ureas and CarbamatesStarting from Arylbromides: Method A

K₂CO₃ (1.5 eq), an amide, urea or carbamate (2 eq), Cul (0.1 eq) andN,N′-dimethyl-1,2-ethanediamine (0.11 eq) were added to a stirredsolution of an arylbromide (1 eq) in dioxane at room temperature underan inert atmosphere, and the reaction was heated at 90-100° C. for 1-5hrs. The mixture was then added to a saturated aqueous solution ofNH₄Cl, and extracted with dichloromethane. The organic phase was washedwith brine, dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude material was purified on SPE cartridge (Silica)using as eluant Cyclohexane/ethyl acetate 8:2, affording the finalcompound (yields ranged from 18 to 99%).

DESCRIPTION 9 1-(3-Acetylphenyl)-2-pyrrolidinone (D9)

The title compound was prepared in 98% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from 1-(3-bromophenyl)ethanone and 2-pyrrolidinone.

MS: (ES) m/z: 204 [MH⁺]. C₁₂H₁₃NO₂ requires 203. ¹H-NMR (300 MHz, CDCl₃)δ(ppm): 8.15 (bs, 1H), 8.0 (dd, 1H), 7.7 (dd, 1H), 7.45 (t, 1H), 3.95(t, 2H), 2.65(m, 2H), 2.60 (s, 3H), 2.2 (m, 2H).

DESCRIPTION 10 1-(3-Acetylphenyl)-2-azetidinone (D10)

The title compound was prepared in 97% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from 1-(3-bromophenyl)ethanone and 2-azetidinone.

MS: (ES) m/z: 190 [MH⁺]. C₁₁H₁₁NO₂ requires 189. ¹H-NMR (300 MHz, CDCl₃)δ(ppm): 7.6 (d, 1H); 7.55(dd, 1H); 7.45(dd, 1H); 7.2 (t, 1H); 3.5 (t,2H), 3.0 (t, 2H), 2.45 (s, 3H)

DESCRIPTION 11 3-(3-Acetylphenyl)-1,3-oxazolidin-2-one (D11)

The title compound was prepared in quantitative yield according to thegeneral procedure for the preparation of the amides, ureas andcarbamates (Method A) starting from 1-(3-bromophenyl)ethanone and1,3-oxazolidin-2-one.

MS: (ES) m/z: 206 [MH⁺]. C₁₁H₁₁NO₃ requires 205. ¹H-NMR (300 MHz, CDCl₃)δ(ppm): 7.95 (m, 2H), 7.7 (dd, 1H), 7.45 (t, 1H), 4.5 (t, 2H), 4.2 (t,2H), 2.6 (s, 3H)

DESCRIPTION 12 1-(3-Acetylphenyl)-2-imidazolidinone (D12)

The title compound was prepared in 18% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from 1-(3-bromophenyl)ethanone and2-imidazolidinone.

MS: (ES) m/z: 205 [MH⁺]. C₁₁H₁₂N₂O₂ requires 204. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 7.8 (m, 2H), 7.54 (dd, 1H), 7.25 (t, 1H), 5.0 (bs, 1H),3.8 (t, 2H), 3.4 (t, 2H), 2.45 (s, 3H).

DESCRIPTION 13 2-(3-Bromophenyl)ethyl methanesulfonate (D13)

The title compound was prepared in 77% yield using a similar procedureto description D4 starting from 2-(3-bromophenyl)ethanol.

MS: (ES/+) m/z: 278 and 280 [MH⁺]. C₉H₁₁BrO₃S requires 277 and 279.¹H-NMR (200 MHz, CDCl₃) δ(ppm): 7.40(2H, m), 7.5 (2H, m), 4.40 (2H, t),3.00 (2H, t), 2.85 (3H, s).

DESCRIPTION 145-{4-[2-(3-Bromophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (D14)

The title compound was prepared in 56% yield using a similar procedureto description D5 starting from 2-methyl-5-(1-piperazinyl)quinoline (D3)and 2-(3-bromophenyl)ethyl methanesulfonate (D13).

MS: (ES/+): m/z: 412 and 410 [MH⁺]. C₂₂H₁₄BrN₃ requires 409 and 411.¹H-NMR (400 MHz, CDCl₃) δ(ppm): 8.29 (1H, d), 7.54 (2H, m), 7.35 (1H, brm), 7.34 (1H, d), 7.23 (2H, m), 7.06 (1H, dd), 2.98 (4H, br s), 2.76(2H, br t), 2.68 (5H, br s), 2.59 (2H, br m), 2.58 (3H, s).

DESCRIPTION 15 2-(3-Nitrophenyl)ethyl 4-nitrobenzenesulfonate (D15)

The title compound was prepared in 68% yield using a similar procedureto description D4 starting from 2-(3-nitro-phenyl)ethanol and4-nitrobenzenesulfonyl chloride.

MS: (ES) m/z: 351 [MH⁺]. C₁₄H₁₂N₂0₇S requires 352. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.3 (m, 2H), 8.05 (d, 1H), 8.0-7.9 (m, 3H), 7.5 (m, 2H),4.4 (t, 2H), 3.1 (t, 2H).

DESCRIPTION 16 7-Chloro-2-methyl-5-(1-piperazinyl)quinoline (D16)

The title compound was prepared from7-chloro-5-hydroxy-2-methylquinoline (WO/0234754) using similarprocedures to descriptions D1, D2 and D3.

MS; (ES) m/z: 262.1 [MH]⁺. C₁₄H₁₆ClN₃ requires 261. ¹H-NMR (300 MHz,d₆-DMSO) δ(ppm): 8.36 (d, 1H), 7.61 (d, 1H), 7.40 (d, 1H), 6.92 (d, 1H3.32 (m, 4H), 2.93 (m, 4H), 2.62 (s, 3H).

DESCRIPTION 177-Chloro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline(D17)

The title compound was prepared in 92% yield using a similar procedureto description D5 starting from7-chloro-2-methyl-5-(1-piperazinyl)quinoline (D16) and2-(3-Nitrophenyl)ethyl 4-nitrobenzenesulfonate (D15).

MS: (ES) m/z: 411 [MH⁺]. C₂₂H₂₃ClN₄O₂ requires 410. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.3 (d, 1H), 8.2 (bd, 1H), 8.05 (bd, 1H), 7.7 (s, 1H),7.55 (d, 1H), 7.4 (t, 1H), 7.2 (d, 1H), 6.95 (s, 1H), 3.1 (bm, 4H), 2.95(t, 2H), 2.8-2.6 (bm, 6H), 2.6 (s, 3H)

DESCRIPTION 183-{2-[4-(7-Chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D18)

The title compound was prepared in 92% yield using a similar procedureto description D6 starting from7-Chloro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline(D17).

MS: (ES) m/z: 381 [MH⁺]. C₂₂H₂₅ClN₄ requires 380. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.25 (d, 1H), 7.65 (s, 1H), 7.2 (d, 1H), 7.05 (t, 1H),6.95 (s, 1H), 6.6 (d, 1H), 6.5 (m, 2H), 3.6 (bs, 2H), 2.8-2.5 (m, 12H),2.65 (s, 3H)

DESCRIPTION 19 [3-(1H-Pyrazol-1-yl)phenyl]acetic acid (D19)

Pyrazole (1.2 eq), Cs₂CO₃ (2.5 eq), Cul (0.5 eq),trans-1,2-cyclohexanediamine (0.6 eq) and dodecane (1 eq), were added toa stirred solution of 3-bromophenylacetic acid (1 eq) in dioxane at roomtemperature under an inert atmosphere. The mixture was irradiated in amicrowave reactor (PersonalChemistry EmryS™ Optimiser, 300 W, 160° C.,20 min), then added to a 1N aqueous solution of NaOH, and extracted withEt₂O. The aqueous phase was acidified to pH=3 with HCl 2N, thenextracted with ethyl acetate; this phase was washed with brine, driedover Na₂SO₄ and the solvent was removed under reduced pressure. Thecrude material was purified on SPE cartridge (Silica) eluting with agradient from Cyclohexane/ethyl acetate 8:2, to Cyclohexane/ethylacetate 1:1, affording the title compound in 65% yield.

MS: (ES) m/z: 203 [MH⁺]. C₁₁H₁₀N₂O₂ requires 202. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 7.9 (m, 1H), 7.75 (m, 1H), 7.65 (m, 1H), 7.55 (d, 1H),7.35 (t, 1H), 7.3-7.1 (m, 2H), 6.55 (m, 1H), 3.7 (s, 2H)

EXAMPLES

General Procedure for the Preparation of Amides Starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6): MethodB

Triethylamine or diisopropylethylamine (1.7 eq) and then an acylchloride (1.5 eq) were added dropwise to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq)in dichloromethane at room temperature under an inert atmosphere. Thereaction was left under stirring for 16 h. The mixture was then washedwith a saturated aqueous solution of NH₄Cl, a saturated aqueous solutionof NaHCO₃, brine, dried over Na₂SO₄ and the solvent was removed underreduced pressure. The crude material was purified on SPE cartridge(Silica) using as eluent a gradient from dichloromethane/MeOH 99/1 todichloromethane/MeOH 98/2 affording the final compound (yields rangedfrom 30 to 80%).

General Procedure for the Preparation of Amides and Their CorrespondingDihydrochloride Salts Starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl] ethyl}aniline (D6):Method C

EDC.HCl (1.5 eq) and HOBt (1.5 eq) were added sequentially to a stirredsolution of a carboxylic acid (1.5 eq) indichloromethane/dimethylformamide (1/1) at room temperature. Thereaction mixture was left under stirring for 30 min then3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq)dissolved in dichloromethane/dimethylformamide (1/1) was added dropwise.The solution was stirred for 16 h then diluted with dichloromethane andwashed with a saturated aqueous solution of NaHCO₃ and brine and thendried over Na₂SO₄. The solution was concentrated under reduced pressureand the residual solvent was removed by means of an SCX cartridge. Thecrude material was purified on SPE cartridge (Silica) eluting from agradient from dichloromethane/MeOH 99/1 to dichloromethane/MeOH 98/2affording the final compound (yields ranged from 20 to 96%).

The free base could be converted into its dihydrochloride salt bydissolving the compound in dichloromethane and adding a 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure affording a crude material which was triturated with Et₂O. Thefinal compound was then recovered by filtration (yield quantitative).

Example 1N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide(E1)

The title compound was prepared in 52% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andacetyl chloride.

MS; (ES) m/z: 389 [MH]⁺. C₂₄H₂₈N₄0 requires 388. ¹H-NMR (500 MHz,d₆-DMSO) δ(ppm): 9.84 (s, 1H), 8.33 (d, 1H), 7.58 (m, 2H), 7.46 (s, 1H),7.39 (m, 2H), 7.19 (t, 1H), 7.10 (dd, 1H), 6.92 (d, 1H), 3.03 (bm, 4H),2.73 (bm, 6H), 2.62 (s+bm, 5H), 2.02 (s, 3H).

Example 2N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)propanamide(E2)

The title compound was prepared in 73% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andpropanoyl chloride.

MS: (ES/+) m/z: 403 [MH⁺]. C₂₅H₃₀N₄O requires 402. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.50 (br s,1H), 7.25 (m, 3H), 7.12 (br, 1H), 7.07 (d, 1H), 6.98 (br d, 1H), 3.20(br m, 4H), 3.00-2.75 (br m, 8H), 2.73 (s, 3H), 2.37 (q, 2H), 1.23 (t,3H)

Example 32-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)propanamide (E3)

The title compound was prepared in 81% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-methylpropanoyl chloride.

MS: (ES/+) m/z: 417 [MH⁺]. C₂₆H₃₂N₄O requires 416. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.55 (m, 2H), 7.25 (m, 3H),7.13 (br s, 1H), 7.08 (d, 1H), 6.98 (br d, 1H), 3.20 (br m, 4H),3.00-2.75 (br m, 8H), 2.73 (s, 3H), 2.48 (m, 1H), 1.25 (d, 6H)

Example 43-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)butanamide (E4)

The title compound was prepared in 64% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and3-methylbutanoyl chloride.

MS: (ES/+) m/z: 431 [MH⁺]. C₂₇H₃₄N₄O requires 430. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.60-7.50 (m, 2H), 7.30-7.20(m, 3H), 7.10 (d, 2H), 7.00 (d, 1H), 3.20 (br s, 4H), 3.00-2.80 (br m,8H), 2.70 (s, 3H), 2.20 (m, 3H), 1.00 (d, 6H).

Example 52,2-Dimethyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)propanamide (E5)

The title compound was prepared in 66% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2,2-dimethylpropanoyl chloride.

MS: (ES/+) m/z: 431 [MH⁺]. C₂₇H₃₄N₄O requires 430. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.55 (t, 2H), 7.30-7.20 (m,4H), 7.10 (d, 1H), 7.00 (m, 1H), 3.20 (brs, 4H), 2.85 (brs, 8H), 2.70(s, 3H), 1.30 (s, 9H)

Example 6N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide(E6)

The title compound was prepared in 60% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andbenzoyl chloride.

MS: (ES/+) m/z: 451 [MH⁺]. C₂₉H₃₀N₄O requires 450. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.87 (m, 2H), 7.80 (br s, 1H), 7.72 (d, 1H), 7.65 (br s, 1H), 7.6-7.4 (m, 5H), 7.30 (t, 1H), 7.27 (m, 1H), 7.08(d, 1H), 7.05 (d, 1H), 3.18 (brs, 4H), 3.00-2.75 (brm, 8H), 2.72 (s,3H).

Example 7N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-phenylacetamide (E7)

The title compound was prepared in 64% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andphenylacetyl chloride.

MS: (ES/+) m/z: 465 [MH⁺]. C₃₀H₃₂N₄O requires 464. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.45-7.15 (m,9H), 7.10-6.95 (m, 3H), 3.70 (s, 2H), 3.10 (br s, 4H), 2.90-2.70 (br s,8H), 2.70 (s, 3H).

Example 83,3-Dimethyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)butanamide (E8)

The title compound was prepared in 62% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and3,3-dimethylbutanoyl chloride.

MS: (ES/+) m/z: 445 [MH⁺]. C₂₈H₃₆N₄O requires 444. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.60-7.45 (m, 2H), 7.30-7.20(m, 3H), 7.15-7.05 (m, 2H), 7.00 (d, 1H), 3.10 (t, 4H), 2.90-2.60 (m,8H), 2.65 (s, 3H), 2.20 (s, 2H), 1.05 (s, 9H).

Example 9N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)cyclohexanecarboxamide (E9)

The title compound was prepared in 30% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andcyclohexanecarbonyl chloride.

MS: (ES/+) m/z: 457 [MH⁺]. C₂₉H₃₆N₄O requires 456. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.60-7.50 (m, 2H), 7.30-7.20(m, 3H), 7.15-7.05 (m, 2H), 7.00 (d, 1H), 3.15 (br s, 4H), 2.95-2.75 (m,8H), 2.70 (s, 3H), 2.20-1.40 (m, 7H), 1.40-1.10 (m, 4H).

Example 105-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-3-isoxazolecarboxamide(E10)

The title compound was prepared in 40% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and5-methyl-3-isoxazolecarbonyl chloride.

MS: (ES/+) m/z: 456 [MH⁺]. C₂₇H₂₉N₅O2 requires 455. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.50 (s, 1H), 8.35 (d, 1H), 7.70 (d, 1H), 7.60 (m, 2H),7.40 (d, 1H), 7.30-7.20 (m, 2H), 7.20-7.10 (t, 2H), 6.50 (s, 1H), 3.15(t, 4H), 2.95-2.70 (m, 8H), 2.70 (s, 3H), 2.50 (s, 3H).

Example 11N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-(2-thienyl)acetamide (E11)

The title compound was prepared in 42% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-thienylacetyl chloride.

MS: (ES/+) m/z: 471 [MH⁺]. C₂₈H₃₀N₄OS requires 470. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.60 (t, 1H), 7.40 (s, 1H),7.30 (dd, 1H), 7.25-7.15 (m, 3H), 7.10-6.90 (m, 5H), 3.90 (s, 2H), 3.15(br s, 4H), 3.00-2.70 (m, 8H), 2.70 (s, 3H).

Example 122-(Methyloxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide (E12)

The title compound was prepared in 62% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and(methyloxy)acetyl chloride.

MS: (ES/+) m/z: 419 [MH⁺]. C₂₅H₃₀N₄O₂ requires 418. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 8.20 (s, 1H), 7.70 (d, 1H), 7.60 (t, 1H),7.50 (s, 1H), 7.35 (d, 1H), 7.30-7.20 (m, 2H), 7.10-6.90 (dd, 2H), 4.00(s, 2H), 3.50 (s, 3H), 3.10 (t, 4H), 2.90-2.70 (m, 8H), 2.70 (s, 3H).

Example 13N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-(phenyloxy)acetamide (E13)

The title compound was prepared in 41% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and(phenyloxy)acetyl chloride.

MS: (ES/+) m/z: 481 [MH⁺]. C₃₀H₃₂N₄O₂ requires 480. ¹H-NMR (400 MHz,CDCl₃) δ(ppm): 8.33 (d, 1H), 7.53 (m, 3H), 7.54 (br s, 1H), 7.46 (br d,1H), 7.37 (d, 1H), 7.30 (dd, 2H), 7.23 (t, 1H), 7.09 (dd, 1H), 6.99 (m,3H), 6.96 (t, 1H), 4.67 (s, 2H), 3.02 (br m, 4H), 2.80-2.60 (m, 8H),2.62 (s, 3H).

Example 14N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)cyclopropanecarboxamide (E14)

The title compound was prepared in 70% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andcyclopropanecarbonyl chloride.

MS: (ES/+) m/z: 415 [MH⁺]. C₂₆H₃₀N₄O requires 414. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.60-7.50 (m, 2H), 7.30 (br s, 1H),7.30-7.20 (m, 3H), 7.05 (d, 1H), 6.95 (brd, 1H), 3.10 (t, 4H), 2.90-2.70(m, 8H), 2.70 (s, 3H), 1.20 (t, 1H), 1.10 (m, 2H), 0.85 (m, 2H).

Example 15N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-oxo-4-imidazolidinecarboxamide(E15)

The title compound was prepared in 51% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-oxo-4-imidazolidinecarboxylic acid.

MS: (ES/+) m/z: 459 [MH⁺]. C₂₆H₃₀N₆O₂ requires 458. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.40 (s, 1H), 8.38(d, 1H), 7.70 (d. 1H), 7.55 (t, 1H),7.50 (d, 1H), 7.40 (dd, 1H), 7.30-7.20 (m, 2H), 7.05 (m, 2H), 5.20 (d,1H), 4.75 (s, 1H), 4.45 (m, 1H), 4.00 (t, 1H), 3.65 (dd, 1H), 3.10 (brs, 4H), 2.95-2.70 (m, 8H), 2.70 (br s, 3H).

Example 16N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-pyrazinecarboxamide (E16)

The title compound was prepared in 89% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-pyrazinecarboxylic acid.

MS: (ES/+) m/z: 453 [MH⁺]. C₂₇H₂₈N₆O requires 452. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 9.65 (s, 1H), 9.50 (m, 1H), 8.80 (d, 1H), 8.60 (t, 1H)8.38 (d, 1H), 7.75 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 7.55 (dd, 1H),7.35 (t, 1H), 7.28 (d, 1H), 7.08 (m, 2H), 3.15 (br s, 4H) 2.95-2.70 (m,8H), 2.70 (br s, 3H).

Example 175-(Methyloxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazole-2-carboxamide(E17)

The title compound was prepared in 30% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and5-(methyloxy)-1,3-oxazole-2-carboxylic acid.

MS: (ES/+) m/z: 472 [MH⁺]. C₂₇H₂₉N₅O₂ requires 471. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.58 (s, 1H), 8.39 (d, 1H), 7.71 (d, 1H), 7.58 (t, 1H)7.60 (d, 1H), 7.48 (dd, 1H), 7.30 (t, 1H), 7.26 (d, 1H), 7.08 (dd, 1H),7.04 (d, 1H), 6.28 (s, 1H), 4.03 (s, 3H), 3.15 (t, 4H) 2.95-2.70 (m,8H), 2.74 (br s, 3H).

Example 18N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,2,3-thiadiazole-4-carboxamide(E18)

The title compound was prepared in 75% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1,2,3-thiadiazole-4-carboxylic acid.

MS: (ES/+) m/z: 459 [MH⁺]. C₂₅H₂₆N₆OS requires 458. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 9.30 (s, 1H), 9.25 (s, 1H), 8.38 (d, 1H), 7.70 (d, 1H),7.68 (d, 1H) 7.58 (t, 1H), 7.55 (dd, 1H), 7.35 (t, 1H), 7.28 (d, 1H),7.10 (m, 2H), 3.15 (br s, 4H) 2.95-2.70 (m, 8H), 2.70 (s, 3H).

Example 192,4-Dimethyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-thiazole-5-carboxamide(E19)

The title compound was prepared in 68% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2,4-dimethyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 486 [MH⁺]. C₂₈H₃₁N₅OS requires 485. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.38 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H) 7.55 (d, 1H),7.35-7.20 (dd, 1H), 7.30 (br s, 1H), 7.10 (m, 2H), 3.15 (t, 4H)2.95-2.70 (m, 8H), 2.72 (s, 6H), 2.70 (s, 3H).

Example 201,5-Dimethyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1H-pyrazole-3-carboxamide (E20)

The title compound was prepared in 35% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

MS: (ES/+) m/z: 469 [MH⁺]. C₂₈H₃₂N₆O requires 468. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.60 (s, 1H), 8.38 (d, 1H), 7.70 (d, 1H), 7.68 (d, 1H),7.58 (t, 1H) 7.45 (d, 1H), 7.35-7.20 (dd, 2H), 7.08 (d, 1H), 7.00 (d,1H), 6.60 (s, 1H), 3.80 (s, 3H), 3.15 (t, 4H) 2.95-2.70 (m, 8H), 2.72(s, 3H), 2.30 (s, 3H).

Example 21N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-4-oxo-4,5,6,7-tetrahydro-1-benzofuran-2-carboxamide(E21)

The title compound was prepared in 20% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and4-oxo-4,5,6,7-tetrahydro-1-benzofuran-3-carboxylic acid.

MS: (ES/+) m/z: 509 [MH⁺]. C₃₁H₃₂N₄O₃ requires 508. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 11.80 (s, 1H), 8.10 (s, 1H), 8.38 (d, 1H), 7.72 (d, 1H)7.70 (d, 1H), 7.65 (dd, 1H), 7.58 (t, 1H), 7.30-7.20 (m, 2H), 7.08 (d,1H), 7.00 (d, 1H), 3.15 (t, 4H), 3.00-2.65 (m, 12H), 2.70 (s, 3H), 2.25(m, 2H).

Example 222-Fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E22)

The title compound was prepared in 96% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-fluorobenzoic acid.

MS: (ES/+) m/z: 469 [MH⁺]. C₂₉H₂₉FN₄O requires 468. ¹H-NMR (500 MHz,d₆-DMSO) δ(ppm): 11.00 (br s, 1H), 10.46 (S, 1H), 8.80 (br s, 1H),8.00-7.72 (m, 4H), 7.65 (t, 1H), 7.58 (q, 1H), 7.52 (d, 1H), 7.73 (br s,1H), 7.37-7.32 (m, 3H), 7.08 (d, 1H), 3.74 (d, 2H), 3.7-3.3 (m, 9H),3.15 (m, 2H), 2.88 (s, 3H)

Example 234-Fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E23)

The title compound was prepared in 82% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and4-fluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.45 min; assay 98.2% a/a; m/z: 469[MH⁺].C₂₉H₂₉FN₄O requires 468. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 11.29(br s, 1H), 10.36 (s, 1H), 8.96 (br s, 1H), 8.08 (m, 2H), 7.99 (br s,1H), 7.86 (br s, 1H), 7.62 (d, 1H), 7.47 (br d, 1H), 7.40 (m, 3H), 7.09(d, 1H), 3.70-3.30 (m, 1OH), 3.18 (dd, 2H), 2.93 (brs, 3H).

Example 242,4-Difluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E24)

The title compound was prepared in 78% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2,4-difluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.51 min; assay >99% a/a; m/z: 487 [MH⁺].C₂₉H₂₈F₂N₄O requires 486. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 11.16 (br s,1H), 10.49 (s, 1H), 8.93 (br s, 1H), 7.70 (br s, 2H), 7.81 (br s, 2H),7.75 (m, 1H), 7.53 (d, 1H), 7.47 (m, 2H), 7.39 (t, 1H), 7.25 (td, 1H),7.10 (d, 1H), 3.70-3.30 (m, 1OH), 2.92 (s, 3H).

Example 253-Fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E25)

The title compound was prepared in 91% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and3-fluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.45 min; assay >99% a/a; m/z: 469 [MH⁺].C₂₉H₂₉FN₄O requires 468. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 11.18 (br s,1H), 10.41 (s, 1H), 8.94 (br s, 1H), 7.97 (br s, 2H), 7.87 (br s, 2H),7.80 (m, 2H), 7.62 (m, 2H), 7.48 (m, 2H), 7.10 (d, 1H), 3.80-3.30 (m,1OH), 3.18 (m, 2H), 2.92 (brs, 3H).

Example 262,5-Difluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E26)

The title compound was prepared in 82% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2,5-difluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.45 min; assay >99% a/a; m/z: 487 [MH⁺].C₂₉H₂₈F₂N₄O requires 486. ¹H-NMR (400 MHz, d6-DMSO) δ(ppm): 11.20 (brs,1H), 10.54 (s, 1H), 8.91 (brs, 1H), 7.96 (br m, 2H), 7.80 (br m, 2H),7.56-7.40 (m, 5H), 7.36 (t, 1H), 7.09 (d, 1H), 3.80-3.10 (m, 12H), 2.90(s, 3H).

Example 273,5-Difluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E27)

The title compound was prepared in 74% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and3,5-difluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.66 min; assay 98.6% a/a; m/z: 487 [MH⁺].C₂₉H₂₈F₂N₄O requires 486. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 11.00 (br s,1H), 10.46 (s, 1H), 8.90 (br s, 1H), 7.93 (s, 2H), 7.90 (br s, 1H), 7.72(m, 2H), 7.86 (s, 1H), 7.62 (d, 1H), 7.56 (m, 1H), 7.45 (brs, 1H), 7.40(t, 1H), 7.12 (d, 1H), 3.76 (d, 2H), 3.70-3.30 (m, 8H), 3.17 (m, 2H),2.99 (br s, 3H).

Example 282,3-Difluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E28)

The title compound was prepared in 86% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2,3-difluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.41 min, assay >99% a/a; m/z: 486 [MH⁺].C₂₉H₂₈F₂N₄O requires 486. ¹H-NMR (400 MHz, d6-DMSO) δ(ppm): 11.00 (br s,1H), 10.62 (s, 1H), 8.95 (br s, 1H), 7.94 (s, 2H), 7.82 (s, 1H), 7.80(br s, 1H), 7.65 (m, 1H), 7.53 (d, 1H), 7.50 (m, 1H), 7.45 (br s, 1H),7.39 (t, 1H), 7.38 (m, 1H), 7.12 (d, 1H), 3.76 (d, 2H), 3.70-3.30 (m,8H), 3.17 (m, 2H), 2.96 (brs, 3H).

Example 292,6-Difluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E29)

The title compound was prepared in 68% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2,6-difluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.24 min; assay >99% a/a; m/z: 486 [MH⁺].C₂₉H₂₈F₂N₄O requires 486. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 10.90 (br s,1H), 10.87 (s, 1H), 8.87 (br s, 1H), 7.92 (s, 2H), 7.84 (s, 1H), 7.79(br s, 1H), 7.62 (m, 1H), 7.48 (d, 1H), 7.50 (m, 1H), 7.44 (br s, 1H),7.39 (t, 1H), 7.27 (m, 2H), 7.12 (d, 1H), 3.76 (d, 2H), 3.70-3.30 (m,8H), 3.17 (m, 2H), 2.88 (brs, 3H).

Example 303,4-Difluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E30)

The title compound was prepared in 92% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and3,4-difluorobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.66 min; assay >99% a/a; m/z: 486 [MH⁺].C₂₉H₂₈F₂N₄O requires 486. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 11.04 (br s,1H), 10.42 (s, 1H), 8.90 (br s, 1H), 8.08 (m, 1H), 7.93 (s, 2H), 7.90(m, 1H), 7.85 (s, 1H), 7.81 (br s, 1H), 7.65 (m, 1H), 7.62 (d, 1H), 7.45(brs, 1H), 7.39 (t, 1H), 7.11 (d, 1H), 3.76 (d, 2H), 3.70-3.30 (m, 8H),3.17 (m, 2H), 2.89 (brs, 3H).

Example 313-(Methyloxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E31)

The title compound was prepared in 83% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and3-(methyloxy)benzoic acid.

HPLC/MS (ES/+): t_(R)=6.39 min; assay >99% a/a; m/z: 481[MH⁺].C₃₀H₃₀N₄O₂ requires 480. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 11.88 (br s,1H), 10.30 (s, 1H), 8.86 (br s, 1H), 7.91 (br s, 2H), 7.87 (br s, 1H),7.78 (br s, 2H), 7.63 (dd, 1H), 7.56 (d, 1H), 7.51 (m, 1H), 7.47 (t,1H), 7.47 (br s, 1H), 7.38 (t, 1H), 7.19 (dm, 1H), 7.09 (d, 1H), 3.86(s, 3H), 3.76 (d, 2H), 3.70-3.25 (m, 8H), 3.17 (m, 2H), 2.88 (brs, 3H).

Example 322-(Methyloxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E32)

The title compound was prepared in 85% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-(methyloxy)benzoic acid.

HPLC/MS (ES/+): t_(R)=6.54 min; assay >99% a/a; m/z: 481 [MH⁺].C₃₀H₃₀N₄O₂ requires 480. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 11.13 (br s,1H), 10.17 (s, 1H), 8.93 (br s, 1H), 7.97 (s, 2H), 7.86-7.78 (br s, 1H),7.64 (dd, 1H), 7.58-7.50(m, 2H), 7.47 (br s, 1H), 7.36 (t, 1H), 7.21 (d,1H), 7.09 (dt, 1H), 7.07 (d, 1H), 3.92 (s, 3H), 3.76 (d, 2H), 3.70-3.30(m, 8H), 3.17 (m, 2H), 2.91(brs, 3H).

Example 334-(Methyloxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E33)

The title compound was prepared in 83% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and4-(methyloxy)benzoic acid.

HPLC/MS (ES/+): t_(R)=6.21 min; assay >99% a/a; m/z: 481 [MH⁺].C₃₀H₃₀N₄O₂ requires 480. ¹H-NMR (500 MHz, d₆-DMSO) δ(ppm): 11.09 (br s,1H), 10.16 (s, 1H), 8.91 (br s, 1H), 7.97 (d, 2H), 7.94 (br s, 2H), 7.84(s, 1H), 7.81 (br s, 1H), 7.60 (d, 1H), 7.44 (br s, 1H), 7.34 (t, 1H),7.05 (m, 3H), 3.83 (s, 3H), 3.74 (br d, 2H), 3.60-3.40 (m, 6H), 3.33(brt, 2H), 3.14 (dd, 2H), 2.89 (brs, 3H).

Example 344-Cyano-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide dihydrochloride salt (E34)

The title compound was prepared in 85% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and4-cyanobenzoic acid.

HPLC/MS (ES/+): t_(R)=6.15 min assay >99% a/a; m/z: 481[MH⁺]. C₃₀H₃₀N₄O₂requires 480. ¹H-NMR (500 MHz, d₆-DMSO) δ(ppm): 10.72 (br s, 1H), 10.56(s, 1H), 8.81 (br s, 1H), 8.11 (d, 2H), 8.04 (d, 2H), 7.86 (brs, 3H),7.75 (brs, 1H), 7.59 (d, 1H), 7.39 (br s, 1H), 7.38 (t, 1H), 7.09 (d,1H), 3.74 (br d, 2H), 3.70-3.40 (m, 6H), 3.28 (br t, 2H), 3.14 (dd, 2H),2.84 (brs, 3H).

Example 353,5-Dimethyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-4-isoxazolecarboxamide(E35)

The title compound was prepared in 56% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and3,5-dimethyl-4-isoxazolecarboxylic acid.

MS: (ES/+) m/z: 470 [MH⁺]. C₂₈H₃₁N₅O₂ requires 469. ¹H-NMR (400 MHz,CDCl₃) δ(ppm): 8.38 (d, 1H), 7.72 (d, 1H), 7.58 (t, 1H), 7.52 (br s,1H), 7.31 (m, 2H), 7.25 (d, 1H), 7.20 (br s, 1H), 7.08 (m, 2H), 3.14 (m,4H), 2.90 (m, 2H), 2.81 (m, 4H), 2.76 (m, 2H), 2.73 (s, 3H), 2.68 (s,3H), 2.52 (s, 3H).

Example 362-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-4-(trifluoromethyl)-1,3-thiazole-5-carboxamidedihydrochloride salt (E36)

The title compound was prepared in 33% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-methyl-4-(trifluoromethyl)-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 540 [MH⁺]. C₂₈H₂₈F₃N₅OS requires 539. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.93 (br s, 1H), 8.82 (br s, 1H), 7.88 (br s, 2H),7.75 (br s, 1H), 7.70 (br s, 1H), 7.43 (d, 1H), 7.40 (br s, 1H), 7.36(t, 1H), 7.10 (d, 1H), 3.8-3.2 (m, 1OH), 3.12 (m, 2H), 2.85 (s, 3H),2.75 (s, 3H).

Example 372-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-thiazole-4-carboxamidedihydrochloride salt (E37)

The title compound was prepared in 52% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-methyl-1,3-thiazole-4-carboxylic acid.

MS: (ES/+) m/z: 472 [MH⁺]. C₂₇H₂₉N₅OS requires 471. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.70 (br s, 1H), 10.15 (s, 1H), 8.77 (br s, 1H), 8.26(s, 1H), 7.87 (brs, 1H), 7.75-7.85 (m, 2H), 7.39 (brs, 1H), 7.34 (t,1H), 7.06 (d, 1H), 3.80-3.20 (m, 10H), 3.12 (dd, 2H), 2.83 (brs, 3H),2.76 (s, 3H).

Example 384-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-thiazole-5-carboxamide dihydrochloride salt

The title compound was prepared in 46% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and4-methyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 472 [MH⁺]. C₂₇H₂₉N₅OS requires 471. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.83 (br s, 1H), 10.28 (s, 1H), 9.13 (s, 1H), 8.86 (brs, 1H), 7.90 (br s, 2H), 7.80-7.74 (br s-s, 2H), 7.50 (d, 1H), 7.43 (brs, 1H), 7.35 (t, 1H), 7.08 (d, 1H), 3.9-3.2 (m, 1OH), 3.13 (dd, 2H),2.87 (br s, 3H), 2.61 (s, 3H).

Example 391-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1H-pyrazole-5-carboxamide dihydrochloride salt (E39)

The title compound was prepared in 60% yield according to the generalprocedure for the preparation of the amides (Method C) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-methyl-1H-pyrazole-5-carboxylic acid.

MS: (ES/+) m/z: 455 [MH⁺]. C₂₇H₃₀N₆O requires 454. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.96 (br s, 1H), 10.27 (s, 1H), 8.85 (br s, 1H),8.0-7.7 (m, 4H), 7.6-7.5 (m, 2H), 7.42 (br s, 1H), 7.6 (t, 1H),7.10-7.08 (m, 2H), 4.09 (s, 3H), 3.74 (d, 2H), 3.51-3.29 (m, 8H), 3.14(m, 2H), 2.87 (s, 3H).

Example 40N-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamidedihydrochloride salt (E40)

The title compound was prepared in 68% yield according to the generalprocedure for the preparation of amides (Method C) starting from1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(D8) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 502 [MH⁺]. C₂₈H₃₁N₅O₂S required 501. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.18 (2H, br s), 8.85 (1H, br s), 7.89 (3H, s), 7.77(1H, br s), 7.53 (1H, d), 7.37 (2H, m), 7.18 (1H, d), 6.36 (1H, br s),5.17 (1H, dd), 3.80-3.20 (1 OH, m), 2.85 (3H, s), 2.64 (3H, s), 2.53(3H, s).

Example 41N-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-methyl-1,3-thiazole-4-carboxamidedihydrochloride salt (E41)

The title compound was prepared in 82% yield according to the generalprocedure for the preparation of amides (Method C) starting from1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(D8) and 2-methyl-1,3-thiazole-4-carboxylic acid.

MS: (ES/+) m/z: 488 [MH⁺]. C₂₇H₂₉N₅O₂S required 487. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.38 (1H, br s), 10.23 (1H, s), 8.88 (1H, br s), 8.30(1H, s), 8.08 (1H, br s), 7.95 (2H, br s), 7.82 (1H, br s), 7.75 (1H,dd), 7.44 (1H, brs), 7.41 (1H, t), 7.22 (1H, d), 6.40 (1H, brs), 5.22(1H, brd), 3.81 (2H, brd), 3.70-3.30 (8H, br m), 2.90 (3H, br s), 2.79ppm (3H, s).

Example 42N-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,5-dimethyl-1H-pyrazole-3-carboxamidedihydrochloride salt (E42)

The title compound was prepared in 95% yield according to the generalprocedure for the preparation of amides (Method C) starting from1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(D8) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid.

MS: (ES/+) m/z: 485 [MH⁺]. C₂₈H₃₂N₆O₂ required 484. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.30 (1H, br s), 9.97 (1H, s), 8.86 (1H, br s), 8.08(1H, s), 7.92 (2H, brs), 7.79 (1H, brs), 7.69 (1H, d), 7.43 (1H, brs),7.38 (1H, t), 7.17 (1H, d), 6.58 (1H, s), 6.38 (1H, br s), 5.19 (1H, brd), 3.86 (3H, s), 3.80 (2H, br m), 3.70-3.20 (8H, br m), 2.89 (3H, brs), 2.33 ppm (3H, s).

Example 43N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)methanesulfonamide(E43)

Methanesulfonyl chloride (8 μL; 1.2 eq) was added dropwise to a solutionof 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6)(0.03g; 1 eq) in pyridine (0.5 mL). The reaction was stirred at r.t.overnight. The reaction mixture was concentrated under reduced pressure,diluted with water (1 mL) and a saturated aqueous solution of sodiumhydrogen carbonate (1 mL), extracted into dichloromethane (3×2 mL),dried over Na₂SO₄ and concentrated under reduced pressure. The crude waspurified by flash chromatography, eluting with a gradient fromdichloromethane to dichloromethane/MeOH (98/2) affording the titlecompound in 44% yield (0.016 g).

MS; (ES) m/z: 425.4 [MH]⁺. C₂₃H₂₈N₄O₂S requires 424. ¹H-NMR (300 MHz,MeOD) δ(ppm): 8.40 (d, 1H), 7.55 (m, 2H), 7.30 (d, 1H), 7.15 (t, 1H),7.10 (m, 2H), 6.90 ((bt, 2H), 3.05 (bt, 4H), 2.85 (s, 3H), 2.83-2.63(bm, 8H), 2.60 (s, 3H).

Example 44N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1-propanesulfonamide(E44)

The title compound was prepared in 62% yield using a similar procedureto example E43 starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andpropanesulfonyl chloride.

MS; (ES) m/z: 453.4 [MH]⁺. C₂₅H₃₂N₄O₂S requires 452. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.60 (t, 1H), 7.30 (m, 2H),7.1 (m, 2H), 7.01 (d, 1H), 3.30 (bm, 6H), 2.80 (bm, 6H), 2.60 (s, 3H),1.80 (m, 2H), 1.0 (t, 3H).

General Procedure for the Preparation of Carbamates and TheirCorresponding Dihydrochloride Salts Starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6): MethodD

Diisopropylethylamine (1.5 eq) and a chloroformate (1.2 eq) were addedsequentially to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6)(1 eq)in dichloromethane at 0° C. The solution was stirred for 1 hr at roomtemperature, then diluted with dichloromethane and washed with asaturated aqueous solution of NH₄Cl and brine and then dried overNa₂SO₄. The solution was concentrated under reduced pressure. The crudematerial was purified on SPE cartridge (Silica) eluting with a gradientfrom dichloromethane/MeOH 99/1 to dichloromethane/MeOH 98/2 affordingthe final compound (yields ranged from 43 to 78%).

The free base could be converted into its dihydrochloride salt bydissolving the compound in dichloromethane and adding a 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure affording a crude material which was triturated with Et₂O. Thefinal compound was then recovered by filtration (yield quantitative).

Example 45 Methyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)carbamate(E45)

The title compound was prepared in 41% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andmethyl chloroformate.

MS; (ES) m/z: 405.4 [MH]⁺. C₂₄H₂₈N₄O₂ requires 404. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.33 (d, 1H), 7.70 (d, 1H), 7.6 (t, 1H), 7.30 (bs, 1H),7.25 (t, 1H), 7.22 (dd, 1H), 7.20 (d, 1H), 7.10 (d, 1H), 6.95 (dd, 1H),6.55 (bs, 1H), 3.8 (s, 3H), 3.28 (bm, 4H), 3.28 (t, 2H), 2.85 (t, 2H),2.75 (bm, 4H), 2.66 (s, 3H).

Example 46 Ethyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)carbamatedihydrochloride (E46)

The title compound was prepared in 79% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andethyl chloroformate.

MS: (ES) m/z: 419 [MH⁺]. C₂₅H₃₀N₄O₂ requires 418. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 11.00 (bs, 1H), 9.74 (s, 1H), 8.95 (s, 1H), 8.00 (s,2H), 7.87 (s, 1H), 7.57 (s, 1H), 7.51 (bs, 1H), 7.36 (m, 2H), 7.02 (d,1H), 4.21 (q, 2H), 3.80 (d, 2H), 3.7-3.3 (m 8H), 3.17 (m, 2H), 2.96 (bs,3H), 1.33 (t, 3H).

Example 47 Propyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)carbamatedihydrochloride (E47)

The title compound was prepared in 78% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andpropyl chloroformate.

MS: (ES) m/z: 433 [MH⁺]. C₂₆H₃₂N₄O₂ requires 432. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.88 (bs, 1H), 9.65 (s, 1H), 8.84 (bs, 1H), 7.89 (bs,2H), 7.76 (bs, 1H), 7.47 (s, 1H), 7.40 (bs, 1H), 7.27-6.92 (m-d, 3H),4.02 (t, 2H), 3.8-3.2 (bm, 10H), 3.07 (dd, 2H), 2.85 (bs, 3H), 1.62 (m,2H), 0.91 (t, 3H).

Example 48 1-Methylethyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)carbamatedihydrochloride (E48)

The title compound was prepared in 77% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-methylethyl chloridocarbonate.

MS: (ES) m/z: 433 [MH⁺]. C₂₆H₃₂N₄O₂ requires 432. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.98 (bs, 1H), 9.58 (s, 1H), 8.86 (bs, 1H), 7.91 (bs,2H), 7.77 (bs, 1H), 7.48 (s, 1H), 7.42 (bs, 1H), 7.25 (m, 2H), 6.91 (d,1H), 4.87 (m, 1H), 3.75-3.2 (bm, 1OH), 3.07 (dd, 2H), 2.87 (bs, 3H),1.24 (d, 6H).

Example 49 2-Methylpropyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl) carbamatedihydrochloride (E49)

The title compound was prepared in 70% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-methylpropyl chloridocarbonate.

MS: (ES) m/z: 447 [MH⁺]. C₂₇H₃₄N₄O₂ requires 446. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.94 (bs, 1H), 9.64 (s, 1H), 8.86 (s, 1H), 7.91 (s,2H), 7.77 (s, 1H), 7.48 (s, 1H), 7.41 (bs, 1H), 7.28 (m, 2H), 6.93 (d,1H), 3.85 (q, 2H), 3.70 (d, 2H), 3.7-3.25 (m, 8H), 3.07 (m, 2H), 2.86(bs, 3H), 1.09 (m, 1H), 0.92 (d, 6H).

Example 50 Phenyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)carbamatedihydrochloride (E50)

The title compound was prepared in 59% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andphenyl chloridocarbonate.

MS: (ES) m/z: 467 [MH⁺]. C₂₉H₃₀N₄O₂ requires 466. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.95 (bs, 1H), 10.27 (s, 1H), 8.84 (s, 1H), 7.90 (s,2H), 7.75 (s, 1H), 7.52 (s, 1H), 7.4-7.2 (m, 8H), 7.00 (d, 1H), 3.71 (d,2H), 3.7-3.3 (m, 8H), 3.09 (m, 2H), 2.86 (bs, 3H)

Example 51 Phenyl methyl(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)carbamatedihydrochloride (E51)

The title compound was prepared in 43% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andphenylmethyl chloridocarbonate.

MS: (ES) m/z: 481 [MH⁺]. C₃₀H₃₂N₄O₂ requires 480. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.8 (bs, 1H), 9.8 (s, 1H), 8.9 (bs, 1H), 7.9 (bs, 2H),7.76 (bs, 1H), 7.50 (bs, 1H), 7.4-7.2 (m, 8H), 6.95 (d, 1H), 5.15 (s,2H), 3.72 (bd, 2H), 3.6-3.2 (m, 8H), 3.09 (m, 2H), 2.86 (bs, 3H).

General Procedure for the Preparation of Ureas or Thioureas and TheirCorresponding Dihydrochloride Salts Starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6): MethodE

An isocyanate or isothiocyanate (1 eq) was added to a stirred solutionof 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1eq) in dichloromethane at room temperature under an inert atmosphere,and the reaction was left under stirring for 16 h. The solution was thenpoured into water and extracted with dichloromethane, the organic phasewas dried over Na₂SO₄ and the solvent was removed under reducedpressure. The crude material was purified on SPE cartridge (Silica)using a gradient from dichloromethane to dichloromethane/MeOH 95/5 aseluant affording the final compound (yields ranged from 30 to 80%).

The free base could be converted into its dihydrochloride salt bydissolving the compound in Et₂O and MeOH and adding an 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure affording a crude material which was triturated with Et₂O. Thefinal compound was then recovered by filtration (yield quantitative).

General Procedure for the Preparation of Ureas and Their CorrespondingDihydrochloride Salts Starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl] ethyl}aniline(D6): MethodF

Triethylamine(6 eq) and solid triphosgene (0.5 eq) were in addedsequentially to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6)(1 eq)in dichloromethane at 0° C. under an inert atmosphere. The reactionmixture was left under stirring for 1 h then diisopropylethylamine andan amine (1.1 eq) dissolved in CH₃CN were added dropwise. The solutionwas stirred for 16 h then diluted with dichloromethane, washed withsaturated aqueous solutions of NaHCO₃ and brine and dried over Na₂SO₄.The solution was concentrated under reduced pressure and the crudematerial was purified on SPE cartridge (Silica) eluting with a gradientfrom dichloromethane to dichloromethane/MeOH 98/2 affording the finalcompound (yields ranged from 20 to 50%).

The free base could be converted into its dihydrochloride salt bydissolving the compound in Et₂O and MeOH and adding an 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure affording a crude material which was triturated with Et₂O. Thefinal compound was then recovered by filtration (yield quantitative).

Example 52N-(3,5-Difluorophenyl)-N′-(3-{2-[4-(2-methylquinolin-5-yl)piperazin-1-yl]ethyl}phenyl)ureadihydrochloride (E52)

The title compound was prepared in 40% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1,3-difluoro-5-isocyanatobenzene.

MS:(ES/+) m/z: 502 [MH⁺] C₂₉H₂₉F₂N₅O requires 501. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.8 (bs, 1H), 9.71 (s, 1H), 9.29 (s, 1H), 8.9(bs, 1H),7.94 (bs, 2H), 7.82 (bs, 1H), 7.53 (s, 1H), 7.45 (bs, 1H), 7.31 (d, 2H),7.20 (dd, 2H), 6.97 (t, 1H), 6.80 (tt, 1H), 3.70 (bd, 2H), 3.7-3.2 (m,8H), 3.13 (dd, 2H), 2.90 (bs, 3H).

Example 53N-(2-Chlorophenyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E53)

The title compound was prepared in 55% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-chloro-2-isocyanatobenzene.

MS: (ES/+) m/z: 500 [MH⁺] C₂₉H₃₀ClN₅O requires 499. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.89 (bs, 1H), 9.66(s, 1H), 8.86 (bs, 1H), 8.41 (s,1H), 8.14 (dd, 1H), 7.90 (bs, 2H), 7.78 (bs, 1H), 7.54 (d, 1H), 7.40(bs, 1H), 7.43 (dd, 1H), 7.27 (m, 3H), 7.02(dt, 1H), 6.93 (m, 1H),3.71(d, 2H), 3.6-3.2 (m, 8H), 3.10 (m, 2H), 2.86 (bs, 3H).

Example 54N-(3-Chlorophenyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E54)

The title compound was prepared in 52% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-chloro-3-isocyanatobenzene.

MS: (ES/+) m/z: 500 [MH⁺] C₂₉H₃₀ClN₅O requires 499. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.53 (bs, 1H), 9.34 (s, 1H), 9.15 (s, 1H), 8.81(bs,1H), 7.88 (bs, 2H), 7.76 (t, 1H), 7.74 (bs, 1H), 7.57 (s, 1H), 7.41 (bs,1H), 7.30 (m, 4H), 7.03 (dt, 1H), 6.96 (bd, 1H), 3.76 (bd, 2H), 3.6-3.2(m, 8H), 3.11 (dd, 2H), 2.85 (bs, 3H).

Example 55N-(3-Fluorophenyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E55)

The title compound was prepared in 48% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-fluoro-3-isocyanatobenzene.

MS: (ES/+) m/z: 484[MH⁺] C₂₉H₃₀FN₅O requires 483. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.7(bs, 1H), 9.47 (s, 1H), 9.24 (s, 1H), 8.75 (bs,1H), 7.81 (bs, 2H), 7.68 (bs, 1H), 7.50 (d+bs, 2H), 7.44 (bs, 1H), 7.31(t, 1H), 7.3-7.24 (m, 2H), 7.09 (d, 1H), 6.89 (d, 1H), 6.74 (td, 1H),3.7-3.2(m, 10H), 3.07 (m, 2H), 2.8 (bs, 3H).

Example 56N-(4-Fluorophenyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E56)

The title compound was prepared in 64% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-fluoro-4-isocyanatobenzene.

MS: (ES/+) m/z: 484[MH⁺]. C₂₉H₃₀FN₅O requires 483. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.49(bs, 1H), 9.40 (s, 1H), 8.96 (s, 1H), 8.77(bs,1H), 7.83 (bs, 2H), 7.71 (bs, 1H), 7.51(bs, 1H), 7.45 (dd, 2H), 7.37(bs, 1H), 7.25 (bd, 2H), 7.10 (t, 2H), 6.90 (bt, 1H), 3.8-3.2(m, 10H),3.06 (dd, 2H), 2.81 (bs, 3H).

Example 57N-(2-Fluorophenyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E57)

The title compound was prepared in 75% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-fluoro-2-isocyanatobenzene.

MS: (ES/+) m/z: 484[MH⁺] C₂₉H₃₀FN₅O requires 483. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10. 9(bs, 1H), 9.36 (s, 1H), 8.8 (bs, 1H), 8.67 (s,1H), 8.11 (t, 1H), 7.86 (bs, 2H), 7.71 (bs, 1H), 7.49 (d, 1H), 7.37 (bs,1H), 7.26 (m, 2H), 7.20 (dd, 1H), 7.07 (dd, 1H), 6.98 (m, 1H), 6.90 (m,1H), 3.69 (d, 2H), 3.5-3.2(m, 8H), 3.09 (m, 2H), 2.82 (bs, 3H).

Example 58N-[4-(Methyloxy)phenyl]-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E58)

The title compound was prepared in 54% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-4-(methyloxy)benzene.

MS: (ES/+) m/z: 496[MH⁺] C₃₀H₃₃N₅O2 requires 495. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.66(bs, 1H), 8.92 (s, 1H), 8.82 (bs, 1H), 8.80(s,1H), 7.88 (bs, 2H), 7.76 (bs, 1H), 7.50(bs, 1H), 7.39 (bs, 1H), 7.24 (m,2H), 6.88 (m, 1H), 7.34 (d, 2H), 6.84(d, 2H), 3.72(m, 2H), 3.69 (s, 3H),3.6-3.0 (m, 10H), 2.81 (bs, 3H).

Example 59N-[3-(Methyloxy)phenyl]-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E59)

The title compound was prepared in 58% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-3-(methyloxy)benzene.

MS: (ES/+) m/z: 496[MH⁺] C₃₀H₃₃N₅O2 requires 495. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.54(bs, 1H), 9.00 (s, 1H), 8.99 (s, 1H), 8.80(bs,1H), 7.91 (t, 1H), 7.85 (bs, 2H), 7.73 (bs, 1H), 7.52(bs, 1H), 7.39 (bs,1H), 7.25 (m, 2H), 7.15 (t, 1H), 6.90(m, 1H), 3.72(m, 2H), 3.69 (s, 3H),3.6-3.0 (m, 10H), 2.81 (bs, 3H).

Example 60N-[2-(Methyloxy)phenyl]-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E60)

The title compound was prepared in 42% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-2-(methyloxy)benzene.

MS (ES/+) m/z: 496[MH⁺] C₃₀H₃₃N₅O₂ requires 495. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.77 (bs, 1H), 9.43 (s, 1H), 8.83 (bs, 1H), 8.26 (s,1H), 8.10 (dd, 1H), 7.88 (bs, 2H), 7.75 (bs, 1H), 7.56 (s, 1H), 7.40(bs, 1H), 7.24 (m, 2H), 7.0-6.8 (m, 4H), 3.86 (s, 3H), 3.72 (d, 2H),3.6-3.2 (m, 8H), 3.08 (m, 2H), 2.84 (bs, 3H).

Example 61N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-[2-(trifluoromethyl)phenyl]ureadihydrochloride (E61)

The title compound was prepared in 63% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-2-(trifluoromethyl)benzene.

MS (ES/+) m/z: 534[MH⁺] C₃₀H₃₀F₃N₅O requires 533. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.83 (bs, 1H), 9.54(s, 1H), 8.83 (bs, 1H), 8.15 (s,1H), 8.14 (dd, 1H), 7.88 (bs, 2H), 7.73 (bs, 1H), 7.64 (d, 1H), 7.59 (t,1H), 7.50 (s, 1H), 7.38 (bs, 1H), 7.25 (m, 3H), 6.91 (m, 1H), 3.69 (m,2H), 3.6-3.2 (m, 8H), 3.07 (m, 2H), 2.83 (bs, 3H).

Example 62N-(3-{2-[4-(6-Methyl-1-naphthalenyl)-1-piperazinyl]ethyl}phenyl)-N′-[3-(trifluoromethyl)phenyl]ureadihydrochloride (E62)

The title compound was prepared in 23% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-3-(trifluoromethyl)benzene.

MS: (ES/+) m/z: 534[MH⁺] C₃₁H₃₁F₃N₄O requires 533. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.41 (bs, 1H), 9.47 (s, 1H), 9.16 (s, 1H), 8.81 (bs,1H), 8.08 (s, 1H), 7.86 (bs, 2H), 7.72 (bs, 1H), 7.61 (s, 1H), 7.6-7.5(m, 2H), 7.41 (bs, 1H), 7.35-7.25 (m, 3H), 6.97 (d, 1H), 3.76 (bm, 2H),3.7-3.3 (bm, 6H), 3.27 (bm, 2H), 3.11 (m, 2H), 2.85 (bs, 3H).

Example 63N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-[4-(trifluoromethyl)phenyl]ureadihydrochloride (E63)

The title compound was prepared in 45% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-4-(trifluoromethyl)benzene.

MS: (ES/+) m/z: 534[MH⁺] C₃₀H₃₀F₃N₅O requires 533. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.34 (bs, 1H), 9.45 (s, 1H), 9.12 (s, 1H), 8.71 (bs,1H), 7.81 (t, 1H), 7.63 (m, 5H), 7.54 (s, 1H), 7.53 (bs, 1H), 7.27 (bs,2H), 6.93 (bd, 1H), 3.8-3.1 (bm, 10H), 3.07 (dd, 2H), 2.79 (bs, 3H).

Example 64N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-propylureadihydrochloride (E64)

The title compound was prepared in 53% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanatopropane.

MS: (ES/+) m/z: 432[MH⁺] C₂₆H₃₃N₅O requires 431. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.5 (bs, 1H), 8.75 (bs, 1H), 8.54 (s, 1H), 7.83 (bs,2H), 7.7 (bs, 1H), 7.45 (s, 1H), 7.38 (bs, 1H), 7.18 (m, 2H), 6.81 (d,1H), 6.23 (bt, 1H), 3.7-3.25 (bd, bt, 4H), 3.6-3.3 (m, 4H), 3.4-3.02 (m,m, 6H), 2.81 (bs, 3H), 1.41 (m, 2H), 0.85 (t, 3H).

Example 65N-(1,1-Dimethylethyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E65)

The title compound was prepared in 79% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-isocyanato-2-methylpropane.

MS: (ES/+) m/z: 446[MH⁺] C₂₇H₃₅N₅O requires 445. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.48 (bs, 1H), 8.75 (bs, 1H), 8.37 (s, 1H), 7.83 (bs,2H), 7.7 (bs, 1H), 7.51 (s, 1H), 7.38 (bs, 1H), 7.17 (t, 1H), 7.04 (dd,1H), 6.79 (d, 1H), 6.08 (s, 1H), 3.71-3.24 (bd, bt, 4H), 3.6-3.3 (m,4H), 3.40 (m, 2H), 3.02 (m, 2H), 2.81 (bs, 3H), 1.27 (s, 9H).

Example 66N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-(phenylmethyl)ureadihydrochloride (E66)

The title compound was prepared in 68% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and(isocyanatomethyl)benzene.

MS: (ES/+) m/z: 480 [MH⁺] C₃₀H₃₃N₅O requires 479. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.74 (bs, 1H), 8.84(bs, 1H), 8.76 (s, 1H), 7.88 (bs,2H), 7.75 (bs, 1H), 7.48 (s, 1H), 7.40 (bs, 1H), 7.32 (m, 4H), 7.20 (m,3H), 6.80 (m, 1H), 6.77 (t, 1H), 4.28(d, 2H), 3.70 (d, 2H), 3.71(d, 2H),3.6-3.2 (m, 8H), 3.04 (m, 2H), 2.85 (bs, 3H).

Example 67N-Methyl-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N-phenylurea dihydrochloride (E67)

The title compound was prepared in 47% yield according to the generalprocedure for the preparation of ureas (Method F) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andN-methylaniline.

MS: (ES/+) m/z: 480 [MH⁺]. C₃₀H₃₃N₅O requires 479. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.9 (bs, 1H), 8.85(bs, 1H), 8.14 (s, 1H), 7.9 (bs,2H), 7.75 (bs, 1H), 7.44-7.36(m, 4H), 7.32-7.25 (m, 3H), 7.24 (d, 1H),7.20 (t, 1H), 6.88(d, 1H), 3.69 (bd, 2H), 3.6-3.2(m, 8H), 3.26 (s, 3H),3.05(m, 2H), 2.85 (bs, 3H).

Example 68N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-phenylureadihydrochloride (E68)

The title compound was prepared in 73% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andisocyanatobenzene.

MS: (ES/+) m/z: 466 [MH⁺] C₂₉H₃₁N₅O requires 465. ¹H-NMR (500 MHz,d6-DMSO) δ(ppm): 10.4 (bs, 1H), 8.95(bd, 2H), 8.75 (bs, 1H), 7.83 (bs,2H), 7.7 (bs, 1H), 7.54 (s, 1H), 7.45 (dd, 2H), 7.38 (bs, 1H), 7.27 (m,4H), 6.96(m, 1H), 6.91 (m, 1H), 3.73 (bd, 2H), 3.6-3.3(m, 6H), 3.24 (t,2H), 3.08 (dd, 2H), 2.81 (bs, 3H).

Example 69N-cyclohexyl-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E69)

The title compound was prepared in 64% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andisocyanatocyclohexane.

MS: (ES/+) m/z: 472 [MH⁺] C₂₉H₃₇N₅O requires 471. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 8.84 (bs, 1H), 8.5 (bd, 1H), 7.9 (bs, 2H), 7.78 (bs,1H), 7.4 (bs, 2H), 7.26 (m, 2H), 6.8 (d, 1H), 6.2 (bd, 1H), 3.7-3.2 (m,11H), 3.03 (dd, 2H), 2.85 (bs, 3H), 1.8 (m, 2H), 1.65 (m, 2H), 1.5 (m,1H), 3H), 1.15 (m, 2H).

Example 70N-Ethyl-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)thioureadihydrochloride (E70)

The title compound was prepared in 74% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andisothiocyanatoethane.

MS:(ES/+) m/z: 434 [MH⁺] C₂₅H₃₁N₅S requires 433. ¹H-NMR (400 MHz,d6-DMSO) δ(ppm): 11.11 (bs, 1H), 9.73 (bs, 1H), 8.93 (bs, 1H), 7.99 (m,3H), 7.82 (bd, 1H), 7.44 (s, 2H), 7.30 (m, 2H), 7.03 (dd, 1H), 3.8-3.2(m, 12H), 3.1(m, 2H), 2.9 (bs, 3H), 1.10 (t, 3H).

Example 71N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-[2-(2-thienyl)ethyl]ureadihydrochloride (E71)

The title compound was prepared in 46% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-(2-isocyanatoethyl)thiophene.

MS: (ES/+) m/z: 500 [MH⁺] C₂₉H₃₃N₅OS requires 499. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.48 (bs, 1H), 8.75 (bs, 1H), 8.64(s, 1H), 7.83 (m,3H), 7.68 (bs, 1H), 7.48 (bs, 1H), 7.36 (bs, 1H), 7.33 (dd, 1H), 7.19(t, 1H), 7.15 (dt, 1H), 6.95 (dd, 1H), 6.89 (m, 1H), 6.82 (dt, 1H), 6.3(t, 1H), 3.71 (bd, 2H), 3.6-3.2 (m, 12H), 3.02(m, 2H), 2.95 (bs, 2H),2.81 (bs, 3H).

Example 72N-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-phenylthioureadihydrochloride (E72)

The title compound was prepared in 59% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andisothiocyanatobenzene.

MS: (ES/+) m/z: 482[MH⁺] C₂₉H₃₁N₅S requires 481. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.55 (bs, 1H), 10.09 (s, 1H), 10.07 (s, 1H), 8.75 (bs,1H), 7.83 (bs, 2H), 7.68 (bs, 1H), 7.51 (s, 1H), 7.49 (d, 2H), 7.4-7.3(m, 2H), 7.35 (bs, 1H), 7.31 (t, 2H), 7.10 (t, 1H), 7.06 (d, 1H), 3.71(d, 2 H), 3.5-3.2 (m, 8H), 3.09 (m, 2H), 2.80 (bs, 3H).

Example 73N-Cyclopentyl-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E73)

The title compound was prepared in 96% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andisocyanatocyclopentane.

MS (ES/+) m/z: 458 [MH⁺] C₂₈H₃₅N₅O requires 457. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.94 (bs, 1H), 8.89 (bs, 1H), 8.51 (s, 1H), 7.93 (bs,2H), 7.80 (bd, 1H), 7.43 (bs, 2H), 7.17 (m,2H), 6.81 (m, 1H), 6.35 (bd,1 H), 3.90 (m, 1H), 3.8-3.2 (bm, 10H), 3.04 (dd, 2H), 2.88 (bs, 3H),1.80 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H), 1.34 (m, 2H).

Example 74 N-(1-Methylpropyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)urea dihydrochloride (E74)

The title compound was prepared in 60% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-isocyanatobutane.

MS: (ES/+) m/z: 446 [MH⁺] C₂₇H₃₅N₅O requires 445. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 11.07 (bs, 1H), 8.91 (bs, 1H), 8.57 (s, 1H), 7.95 (bm,2H), 7.81 (bd, 1H), 7.43 (bs, 2H), 7.17 (m,2H), 6.80 (m, 1H), 6.17 (bd,1H), 3.8-3.2 (bm, 11H), 3.06 (dd, 1H), 2.89 (bs, 3H), 1.39 (q, 1H), 1.04(d, 3H), 0.85 (t, 3H).

Example 75N-Ethyl-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E75)

The title compound was prepared in 95% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andisocyanatoethane.

MS: (ES/+) m/z: 418 [MH⁺] C₂₅H₃₁N₅O requires 417. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.89 (bs, 1H), 8.60 (bs, 1H), 8.90 (s, 1H), 7.92 (bs,2H), 7.80(bs, 1H), 7.44 (s, 2H), 7.19 (m, 2H), 6.81 (m, 1H), 3.71 (d, 2H), 3.6-3.2 (m, 10H), 3.07 (m, 2H), 2.87 (bs, 3H), 1.02 (t, 3H).

Example 76N-(2-Methylphenyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E76)

The title compound was prepared in 60% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-2-methylbenzene.

MS: (ES/+) m/z: 480 [MH⁺] C₃₀H₃₃N₅O requires 479. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.65 (bs, 1H), 9.37 (s, 1H), 8.80 (d, 1H), 8.13 (s,1H), 7.85 (m, 2H), 7.79 (d, 1H), 7.72 (bs, 1H), 7.52 (s, 1H), 7.37 (bs,1 H), 7.25 (m, 1H), 7.09 (m, 2H), 6.88 (m, 2H), 3.69 (d, 2H), 3.6-3.2(m, 6 H), 3.06 (m, 2H), 2.81 (bs, 3H), 2.22 (s, 3H).

Example 77N-[3,5-Bis(trifluoromethyl)phenyl]-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)ureadihydrochloride (E77)

The title compound was prepared in 60% yield according to the generalprocedure for the preparation of ureas (Method E) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and1-isocyanato-3,5-bis(trifluoromethyl)benzene.

MS:(ES/+) m/z: 602 [MH⁺] C₃₁H₂₉F₆N₅O requires 601. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.6 (b, 1H), 10.06 (s, 1H), 9.41 (s, 1H), 8.85 (bs,1H), 8.15 (s, 2H), 7.9 (bs, 2H), 7.78 (bs, 1H), 7.66 (s, 1H), 7.6 (s,1H), 7.43 (bs, 1H), 7.32 (d, 2H), 6.99 (t, 1H), 3.76 (bd, 2H), 3.4-3.7(bm, 6 H), 3.29 (t, 2 H), 3.13 (dd, 2H), 2.87 (bs, 3H).

Example 78N-Methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-phenylureadihydrochloride salt.

The title compound was prepared in 85% yield according to generalprocedure for the preparation of ureas (Method E) starting fromN-methyl-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D7) and isocyanatobenzene.

MS: (ES) m/z: 480 [MH⁺]. C₃₀H₃₅Cl₂N₅O requires 479. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.90 (1H, bs), 8.80 (1H, bs), 8.18 (1H, s), 7.88 (2H,bs), 7.75 (1H, bs), 7.43 (2H, d), 7.37(1H, d), 7.43 (1H, d), 7.30 (1H,bs), 7.25-7.15 (2H, m), 7.19 (2H, dt), 6.92 (1H, tt), 3.69 (4H, brd),3.60-3.20 (6H, m), 3.28 (3H, s), 3.12 (2H, m), 2.85 (2H, s).

Example 791-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-3-phenyl-2-imidazolidinonedihydrochloride salt (E79)

The title compound was prepared in 50% yield according to the generalprocedure for the preparation of ureas from arylbromides (Method A)starting from5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (D14) and1-phenyl-2-imidazolidinone using 3.0 equiv. of Cul andN,N′-dimethylethylenediamine.

MS: (ES/+) m/z: 492 [MH⁺]. C₃₁H₃₃N₅O requires 491. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm):11.0 (1H, br s), 8.90 (1H, br s), 7.94 (2H, br s), 7.80(1H, br s), 7.71 (1H, br s), 7.66 (2H, d), 7.51 (1H, br d), 7.39 (1H,m), 7.09 (1H, m), 7.05 (1H, d), 4.01 (4H, s), 3.80-3.20 (10H, m), 3.17(2H, dd), 2.90 (2H, br s).

Example 801-[4-(Methyloxy)phenyl]-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone dihydrochloride salt (E80)

The title compound was prepared in 16% yield according to the generalprocedure for the preparation of ureas from arylbr omides (Method A)starting from5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (D14) and1-[4-(methyloxy)phenyl]-2-imidazolidinone using 6.0 equiv. of Cul andN,N′-dimethylethylenediamine, which were added in two different portionsof 3.0 equiv.

MS: (ES/+) m/z: 522 [MH⁺]. C₂₃H₃₅N₅O₂ requires 521. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.57 (1H, br s), 8.76 (2H, br s), 7.84 (2H, br s),7.69 (1H, br s), 7.68 (1H, s), 7.52 (d, 2H), 7.46 (d, 1H), 7.37 (br s,1H), 7.36 (t, 1H), 7.01 (1H, d), 6.94 (2H, d), 3.95 (4H, s), 3.74 (3H,s), 3.72-3.13 (12H, m), 2.82 (3H, br s).

Example 811-[2-(Methyloxy)phenyl]-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride salt (E81)

The title compound was prepared in 65% yield according to the generalprocedure for the preparation of ureas from arylbromides (Method A)starting from5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (D14) and1-[2-(methyloxy)phenyl]-2-imidazolidinone using 6.0 equiv. of Cul andN,N′-dimethylethylenediamine, which were added in two different portionsof 3.0 equiv.

MS: (ES/+) m/z: 522 [MH⁺]. C₂₃H₃₅N₅O₂ requires 521. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.93 (1H, br s), 8.88 (1H, br s), 7.93 (2H, br s),7.79 (1H, br s), 7.67 (1H, br s), 7.48 (1H, dd), 7.44 (1H, br s), 7.37(1H, t), 7.32 (2H, m), 7.14 (1H, br d), 7.01 (2H, m), 4.00 (2H, dd),3.86 (2H, m), 3.84 (3H, s), 3.75 (2H, br d), 3.70-3.20 (8H, m), 3.15(2H, dd), 2.89 (3H, br s).

Example 821-(2-Methylphenyl)-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone dihydrochloride salt (E82)

The title compound was prepared in 65% yield according to the generalprocedure for the preparation of ureas from arylbromides (Method A)starting from5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (D14) and1-(2-methylphenyl)-2-imidazolidinone using 3.0 equiv. of Cul andN,N′-dimethylethylenediamine.

MS: (ES/+) m/z: 506 [MH⁺]. C₃₂H₃₅N₅O requires 505. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.90 (1H, br s), 8.90 (1H, br s), 7.93 (br s, 2H),7.80 (1H, br s), 7.67 (1H, s), 7.49 (dd, 1H), 7.44 (1H, br s), 7.40-7.20(m, 5H), 7.02 (1H, dd), 4.03 (2H, t), 3.88 (2H, t), 3.74 (2H, br d),3.70-3.20 (8H, m), 3.15 (2H, dd), 2.89 (3H, br s), 2.26 (3H, s).

Example 831-(3-Methylphenyl)-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride salt (E83)

The title compound was prepared in 55% yield according to the generalprocedure for the preparation of ureas from arylbromides (Method A)starting from5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (D14) and1-(3-methylphenyl)-2-imidazolidinone using 10 mol % of Cul andN,N′-dimethylethylenediamine.

MS: (ES/+) m/z: 506 [MH⁺]. C₃₂H₃₅N₅O requires 505. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.80 (1H, br s), 8.85 (1H, br s), 7.89 (2H, br s),7.76 (1H, br s), 7.70 (1H, s), 7.48 (1H, s), 7.45 (1H, d), 7.42 (2H, brm), 7.37 (1H, t), 7.24 (1H, t), 7.02 (1H, d), 6.89 (1H, d), 3.98 (4H,s), 3.74 (2H, br d), 3.60-3.30 (8H, m), 3.14 (2H, dd), 2.86 (3H, br s),2.32 (3H, s).

Example 841-(4-Methylphenyl)-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride salt (E84)

The title compound was prepared in 65% yield according to the generalprocedure for the preparation of ureas from arylbromides (Method A)starting from5-{4-[2-(3-bromophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (D14) and1-(4-methylphenyl)-2-imidazolidinone using 3.0 equiv. of Cul andN,N′-dimethylethylenediamine.

MS: (ES/+) m/z: 506 [MH⁺]. C₃₂H₃₅N₅O requires 505. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm):10.94 (1H, br s), 8.90 (1H, br s), 7.94 (2H, br s), 7.80(1H, br s), 7.71 (1H, br s), 7.53 (2H, d), 7.49 (22H, d), 7.45 (1H, brs), 7.38 (1H, t), 7.19 (2H, d), 7.04 (1H, d), 3.99 (4H, s), 3.75 (2H, brd), 3.70-3.30 (8H, m), 3.16 (2H, dd), 2.90 (3H, br s), 2.00 (3H, s).

General Procedure for the Synthesis of Cyclic Ureas and Carbamates andtheir Corresponding Dihydrochloride Salts Starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D3): MethodG

Diisopropylethylamine (1.5 eq) and a chloroformate or isocyanate (1.2eq) were added sequentially to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (1 eq) indichloromethane at 0° C. The solution was stirred for 1 hr at roomtemperature, then diluted with dichloromethane and washed with asaturated aqueous solution of NH₄Cl and br ine and then dried overNa₂SO₄. The solution was concentrated under reduced pressurye. The crudematerial was dissolved in dimethylformamide, cooled to 0° C., and NaH(1.1 eq) was added portionwise under an inert atmosphere. The mixturewas stirred for 2 hrs at room temperature, then the solvent was removedby means of an SCX cartridge. The crude material was purified on SPEcartridge (Silica) eluting with a gradient from dichloromethane/MeOH99/1 to dichloromethane/MeOH 98/2 affording the final compound (yieldsranged from 22 to 87%).

The free base could be converted into its dihydrochloride salt bydissolving the compound in Et₂O and MeOH and adding an 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure affording a crude material which was triturated with Et₂O. Thefinal compound was then recovered by filtration (yield quantitative).

Example 851-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E85)

The title compound was prepared in 22% yield according to the generalprocedure for the synthesis of cyclic ureas and carbamates (Method G)starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D3) and1-chloro-2-isocyanatoethane, via the free base1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone.

MS: (ES) m/z: 416 [MH⁺]. C₂₅H₂₉N₅O requires 415. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.60 (bs, 1H), 8.77 (s, 1H), 7.85 (s, 2H), 7.71 (s,1H), 7.59 (s, 1H), 7.38 (dd, 1H), 7.28 (t,1H), 6.96 (bs, 1H), 6.92 (d,1H), 3.83 (m, 2H), 3.71 (d, 2H), 3.7-3.2 (m, 10H), 3.08 (m, 2H), 2.82(bs, 3H).

Alternative Preparation of1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone

Methyl (3-aminophenyl)acetate hydrochloride

3-Aminophenylacetic acid (1 wt) was suspended in methanol (5 vol) undernitrogen at 20° C. Chlorotrimethylsilane (1.26 vol) was added over 60minutes at 20° C. The reaction mixture was stirred at 20° C. for onehour, then concentrated under reduced pressure to 3 vol. Methyl-t-butylether (4 vol) was added and the resulting suspension was stirred at roomtemperature for 18 hours. The solid was collected by filtration, washingwith methyl-t-butyl ether (4×1 vol). The material was dried in oven at40° C. for 5 hours to give the title compound.

MS: (ES) m/z: 166 [MH⁺]. C₉H₁₁NO₂ requires 165. ¹H-NMR (300 MHz,d₆-DMSO) δ(ppm): 7.40 (m, 1H), 7.19 (m, 3H), 3.74 (s, 2H), 3.58 (s, 3H).

Methyl [3-(2-oxo-1-imidazolidinyl)phenyl]acetate

Methyl (3-aminophenyl)acetate hydrochloride was suspended indichloromethane (7 vol) under nitrogen. Diisopropylethylamine (1.04 vol)was added at 20° C. over 30 minutes, and the reaction mixture wasstirred for 30 minutes at 20° C. 2-Chloroethyl isocyanate (0.44 vol) wasadded dropwise at 20° C. over 100 minutes. The reaction mixture wasstirred at 20° C. for three hours. A saturated solution of ammoniumchloride (5 vol) was added dropwise over 10 mins and the resultantmixture was stirred for ten minutes. The organic phase was separated andwashed with water (5 vol). Tetrahydrofuran (2×3 vol) was added and themixture was concentrated to 2 vol. Dry tetrahydrofuran (5 vol) wasadded, and the mixture was concentrated to 2 vol. Dry THF (3 vol) wasadded, under nitrogen at 20° C. The reaction mixture was cooled to 0°C., and potassium tert-butoxide (0.56 wt) was added portion-wise in 5stages, allowing 20 minutes between two subsequent additions. Thereaction mixture was stirred at 20° C. for one hour. Hydrochloric acid(0.5N, 2 vol) was added dropwise over 20 minutes. Ethyl acetate (10 vol)was added and the organic phase was separated. The organic layer waswashed with aqueous sodium hydrogencarboante solution (4%, 2 vol) andbrine (2 vol), and the organic layer was then evaporated to drynessunder vacuum to give the title compound (overall yield: 90% w/w).

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 7.50-7.45 (m, 2H), 7.30 (m, 1H), 7.00(d, 1H), 4.98 (br. s,1H), 4.95 (t, 2H), 3.68 (s, 3H), 3.62 (s, 2H), 3.54(t, 2H).

1-[3-(2-Hydroxyethyl)phenyl]-2-imidazolidinone

Methyl [3-(2-oxo-1-imidazolidinyl)phenyl]acetate was dissolved in drydichloromethane (10 vol). Lithium borohydride (2M solution in THF, 4.3vol) was added dropwise over 1 hour at 20° C. The resulting suspensionwas stirred at 20° C. for 2.5 hours. Water (2 vol) is added dropwise at20° C. over 60 minutes. The resulting suspension was concentrated to 2vol and aqueous ammonium chloride solution (7%, acidity corrected with10% hydrochloric acid to pH 3, 3 vol) was added. The suspension wasstirred at 20° C. for 2 hours then filtered. The filter-cake was washedthoroughly with aqueous ammonium chloride solution (7%, aciditycorrected with 10% hydrochloric acid to pH 3, 2 vol) and water (2 vol)until the filtrate had an acidity of pH 7. The filter-cake was dried at80° C. to give the title compound (75% th.).

¹H-NMR (300 MHz, d₆-DMSO) δ(ppm): 7.36-7.27 (m, 2H), 7.19 (t, 1H), 7.86(m, 1H), 7.81 (d,1H), 4.58 (br. s,1H), 3.60 (t, 2H), 3.52 (m, 2H), 3.35(t, 2H), 2.64 (t, 2H).

2-[3-(2-Oxo-1-imidazolidinyl)phenyl]ethyl methanesulfonate

1-[3-(2-Hydroxyethyl)phenyl]-2-imidazolidinone was suspended in DMF (4vol) and heated to 35° C. until a clear solution was obtained.Triethylamine (1 vol) was added dropwise at 30° C. over 15 minutes. Themixture was cooled to 20° C. and methanesulfonyl chloride (0.46 vol) wasadded 30 mins. The resulting suspension was stirred at 20° C. for 15minutes. Dichloromethane (10 vol) was added, and the organic layer waswashed with brine/water (1:1) (5 vol), and then water (3×5 vol). Theorganic phase was concentrated to 1 vol, and methanol was added (4 vol),if complete dissolution was not obtained, the mixture was heated to 35°C. in order to dissolve the solid. Methyl-t-butyl ether (10 vol) wasadded and the suspension was left to stand for 18 hours at roomtemperature. The suspension was filtered; the filter-cake was washedwith methyl-t-butyl ether (2 vol). The solid was dried at 40° C. for 18hours to give the title compound (70% th).

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 7.54 (s, 1H), 7.40-7.25 (m, 2H), 6.92(d, 1H), 4.72 (br. s, 1H), 4.41 (t, 2H), 3.92 (t, 2H), 3.60 (t, 2H),3.09 (t, 2H), 2.87 (s, 3H).

Alternatively, 1-[3-(2-hydroxyethyl)phenyl]-2-imidazolidinone wassuspended in acetonitrile (5 vol) at room temperature and undernitrogen. Triethylamine (1 vol) was added dropwise over 15 minutes. Themixture was cooled to 0° C. and methanesulfonyl chloride (0.73 vol) wasadded over 30 minutes. The reaction mixture was stirred at roomtemperature for 2 hours, then diluted with ethyl acetate (10 vol). Themixture was washed with a saturated solution of ammonium chloride (2×3vol), followed by water-brine 1:1 (2×3 vol). The organic phase wasconcentrated to 5 vol, ethyl acetate (5 vol) was added and the solutionwas evaporated to dryness, yielding the title compound as acream-coloured solid (yield: 90% th).

2-Methyl-5-quinolinyl trifluoromethanesulfonate

5-Hydroxy-2-methylquinoline hydrobromide (WO2002034754, Chem. Abstr.136:355241, 1 wt, 1 eq) was suspended in ethyl acetate (20 vol) and asaturated solution of sodium hydrogen carbonate (7 vol) was added. Theorganic layer was washed with a saturated solution of sodium hydrogencarbonate (7 vol) and the two layers were separated. The organic layerwas concentrated to 2 vol then ethyl acetate (2×3 vol) was added and themixture was concentrated to 2 vol each time. Toluene was added (2×10vol) and the mixture was concentrated to 2 vol each time to give asuspension of 5-hydroxy-2-methylquinoline. Toluene (9 vol) and pyridine(0.68 vol, 1.33 eq) were added under nitrogen at room temperature. Themixture was cooled to 0° C. and triflic anhydride (1.27 vol, 1.2 eq) wasadded dropwise maintaining the temperature at 0° C., then warming to 25°C. for 3 hours. A saturated aqueous solution of ammonium chloride (7vol) was added and the mixture was stirred for 10 minutes. The twolayers were separated and the organic layer was washed with water (7vol), a 4% solution of sodium hydrogencarbonate (7 vol), water (7 vol),then concentrated to 3 volumes. Toluene (2×7 vol) was added and themixture concentrated to 3 volumes to give a crude brown solution of thetitle compound (70% th), which was used without further purification.

1,1-Dimethylethyl 4-(2-methyl-5-quinolinyl)-1-piperazinecarboxylate

A solution of 2-methyl-5-quinolinyl trifluoromethanesulfonate (1 wt, 1eq) in toluene (7 vol) was degassed under reduced pressure then flushedwith nitrogen. To the mixture were added N-Boc-piperazine (1.05 eq),milled cesium carbonate (1.5 eq),(+/−)-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 0.15 eq) andpalladium acetate (0.05 eq). The resulting mixture was stirred at 95° C.for 16 hours. The solution was cooled and concentrated to approx. 4 voland 10 vol of cyclohexane were added giving a suspension. The suspensionwas stirred for 30 minutes and filtered over a pad of Silica Gel (approx2.5 vol). The filtrate was washed with 10 vol of water and concentratedunder reduced pressure to give the title compound as a brown solid,which was carried through directly to the next stage.

2-Methyl-5-(1-piperazinyl)quinoline

To a solution of 1,1-dimethylethyl4-(2-methyl-5-quinolinyl)-1-piperazinecarboxylate in 2-propanol (3 vol)was added dropwise hydrochloric acid (37%, 3 vol). The mixture wasstirred at 40° C. for 1.5 hours then concentrated. Water (30 vol) wasadded and the solution was extracted with ethyl acetate (3×20 vol). Theaqueous layer was basified with an aqueous sodium carbonate solutionthen extracted with dichloromethane (5×40 vol). The combined organicextracts were dried and evaporated to give the title compound as anoff-white solid (80% th, 2 steps).

1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(E85)

2-[3-(2-Oxo-1-imidazolidinyl)phenyl]ethyl methanesulfonate (1.32 wt) and2-methyl-5-(1-piperazinyl)quinoline (1 wt.) were suspended inacetonitrile (5 vol) at room temperature under nitrogen.Diisopropylethylamine (1.53 vol) was added dropwise over 30 minutes, andthe mixture was then stirred at 75° C. for 4 hours. The reaction mixturewas cooled to room temperature, concentrated to 2 vol, and diluted withethyl acetate (7 vol). The organic layer was washed with saturatedaqueous ammonium chloride solution (2×3 vol), followed by water (1×3vol). The organic layer was evaporated to dryness, yielding the titlecompound as a brown foam (70% th).

Sulfate Salt of E85:1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonesulfate

1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(300 mg, 1 wt) is suspended in methanol (6.0 ml, 20 vol) at roomtemperature under nitrogen. A solution of sulfuric acid (71 mg, 1 eq) inmethanol is dosed. The clear solution is seeded and solidcrystallization is observed. The slurry is stirred 16 hrs at roomtemperature. The solid is filtered and dried at room temperature undervacuum to give the desired salt.

1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonemay exist as two different physical forms, form 1 or form 2.1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone,form 1

The free-base was completely dissolved in DCM (10 volumes) at reflux.The mixture was concentrated under vacuum (rotary evaporator) at 40° C.(external temperature), until crystallisation initiated (mixture reducedto 2-3 volumes). The suspension was cooled to 25° C., then methyltert-butyl ether (10 volumes) was added with stirring. The suspensionwas stirred at 25° C. for 18 hours. The precipitate was filtered off,washed with methyl tert-butyl ether (1 vol) and dried at 40° C. for 18hours to give the title compound; m.p. 170° C.

1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone,form 2

The free-base was completely dissolved in DCM (10 volumes) at reflux.The solution was cooled to 25° C., then methyl tert-butyl ether (10volumes) was added with stirring. The suspension was stirred at 25° C.overnight. The precipitate thus formed was filtered off, washed withmethyl tert-butyl ether-DCM (1:1, 2×1 volume) and dried at 40° C. for 18hours to give the title compound; m.p. 164° C.

Example 863-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride (E86)

The title compound was prepared in 81% yield according to the generalprocedure for the synthesis of cyclic ureas and carbamates (Method G)starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D3) and(2-bromoethyl)carbamic chloride.

MS: (ES) m/z: 417 [MH⁺]. C₂₅H₂₈N₄O₂ requires 416. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.99 (bs, 1H), 8.87 (bm, 1H), 7.91 (bm, 2H), 7.79 (bm,1H), 7.57 (s, 1H), 7.40 (m, 3H), 7.08 (d, 1H), 4.43 (t, 2H), 4.07 (t,2H), 3.72-3.3 (m, 10H), 3.15 (m, 2H), 2.87 (bs, 3H).

Example 871-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)tetrahydro-2(1H)-pyrimidinonedihydrochloride (E87)

The title compound was prepared in 87% yield according to the generalprocedure for the synthesis of cyclic ureas and carbamates (Method G)starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D3) and1-chloro-3-isocyanatopropane.

MS: (ES) m/z: 430 [MH⁺]. C₂₆H₃₁N₅O requires 429. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 11.05 (bs, 1H), 8.94 (s, 1H), 7.97 (s, 2H), 7.84 (d,1H), 7.46 (bs, 1H), 7.30 (m, 2H), 7.19 (dd, 1H), 7.08 (d, 1H), 6.58 (s,1H), 3.70 (bm, 4H), 3.63 (t, 2H), 3.6-3.3 (bm, 6H), 3.24 (t, 2H), 3.12(m, 2H), 2.91 (s, 3H), 1.95 (t, 2H).

Example 883-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)tetrahydro-2H-1,3-oxazin-2-onedihydrochloride (E88)

The title compound was prepared in 75% yield according to the generalprocedure for the synthesis of cyclic ureas and carbamates (Method G)starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D3) and(3-chloropropyl)carbamic chloride. MS: (ES) m/z: 431 [MH⁺]. C₂₆H₃₀N₄O₂requires 430. ¹H-NMR (400 MHz, d₆-DMSO) δ(ppm): 10.89 (bs, 1H), 8.84(bm, 1H), 7.89 (bm, 2H), 7.76 (bm, 1H), 7.40 (m, 4H), 7.31 (s, 1H), 4.32(t, 2H), 3.72-3.3 (m, 10H), 3.66 (t, 2H), 3.13 (m, 2H), 2.85 (bs, 3H),2.10 (m, 2H).

General Procedure for the Synthesis of Cyclic Amide, Urea, and CarbamateDerivatives of 1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol (D8) andtheir Corresponding Dhydrochloride Salts Starting Form1-(3-acetylphenyl)-2-cyclic Amides, Ureas and Carbamates. Method H

AlCl₃ (1% w/w) and then bromine (1 eq) was added dropwise to a stirredsolution of a 1-(3-acetylphenyl)-2-cyclic amide, urea or carbamate (1eq) in Et₂O or dichloromethane at 0° C. The solution was stirred for 1hr at room temperature, then diluted with dichloromethane and washedwith a saturated aqueous solution of NaHCO₃, a saturated aqueoussolution of NH₄Cl and brine and then dried over Na₂SO₄. The solution wasconcentrated under reduced pressure. The crude material was dissolved indimethylformamide and 2-methyl-5-(1-piperazinyl)quinoline (D3) (1 eq)and Na₂CO₃ (1.5 eq) were added. The solution was stirred for 2-4 hrs atroom temperature. MeOH was then added in equal volume with respect todimethylformamide, followed by NaBH₄ (2 eq) and the solution was stirredfor 15 min at room temperature. The solvent was removed by means of anSCX cartridge. The crude material was purified on SPE cartridge (Silica)eluting with a gradient from dichloromethane/MeOH 99/1 todichloromethane/MeOH 98/2 affording the final compound (yields rangedfrom 39 to 71%).

The free base could be converted into its dihydrochloride salt bydissolving the compound in Et₂O and MeOH and adding an 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure affording a crude material which was triturated with Et₂O. Thefinal compound was then recovered by filtration (yield quantitative).

Example 891-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-pyrrolidinonedihydrochloride (E89)

The title compound was prepared in 25% yield according to the generalprocedure for the synthesis of cyclic amide, urea and carbamatederivatives of1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(Method H) starting from 1-(3-acetylphenyl)-2-pyrrolidinone (D9) and2-methyl-5-(1-piperazinyl)quinoline (D3).

MS: (ES) m/z: 431 [MH⁺]. C₂₆H₃₀N₄O₂ requires 430. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.2 (bs, 1H), 8.8 (bs, 1H), 7.86 (bs, 2H), 7.81 (s,1H), 7.73 (bs, 1H), 7.54 (dd, 1H), 7.40 (t, 1H), 7.38 (bs, 1H), 7.20 (d,1H), 6.36 (bs, 1H), 5.18 (dd, 1H), 3.83 (t, 2H), 3.76 (bt, 2H), 3.7-3.2(m, 8H), 2.83 (bs, 3H), 2.5 (m, 2H), 2.07 (q, 2H).

Example 901-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-azetidinonedihydrochloride (E90)

The title compound was prepared in 39% yield according to the generalprocedure for the synthesis of cyclic amide, urea and carbamatederivatives of1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(Method H) starting from 1-(3-acetylphenyl)-2-azetidinone (D10) and2-methyl-5-(1-piperazinyl)quinoline (D3).

MS: (ES) m/z: 417 [MH⁺]. C₂₅H₂₈N₄O₂ requires 416. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.35 (bs, 1H), 8.84 (bs, 1H), 7.91 (bs, 2H), 7.77 (bs,1H), 7.51 (s, 1H), 7.40 (t+bs, 2H), 7.23 (d, 1H), 7.15 (d, 1H), 6.38(bs, 1H), 5.19 (d, 1H), 3.8-3.2 (m, 12H), 3.09 (t, 2H), 2.86 (bs, 3H).

Example 913-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride (E91)

The title compound was prepared in 34% yield according to the generalprocedure for the synthesis of cyclic amide, urea and carbamatederivatives of1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(Method H) starting from 1-(3-acetylphenyl)-1,3-oxazolidin-2-one (D11)and 2-methyl-5-(1-piperazinyl)quinoline (D3).

MS: (ES) m/z: 433 [MH⁺]. C₂₅H₂₈N₄O₃ requires 432. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.3 (bs, 1H), 8.8 (bs, 1H), 7.89 (bs, 2H), 7.76 (bs,2H), 7.44 (m, 3H), 7.20 (d, 1H), 6.4 (bs, 1H), 5.21 (dd, 1H), 4.45 (t,2H), 4.06 (t, 2H), 3.76 (bt, 2H), 3.7-3.2 (m, 8H), 2.85 (bs, 3H).

Example 921-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E92)

The title compound was prepared in 26% yield according to the generalprocedure for the synthesis of cyclic amide, urea and carbamatederivatives of1-(3-aminophenyl)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethanol(Method H) starting from 1-(3-acetylphenyl)-2-imidazolidinone (D12) and2-methyl-5-(1-piperazinyl)quinoline (D3).

MS: (ES) m/z: 432 [MH⁺]. C₂₅H₂₉N₅O₂ requires 431. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.2 (bs, 1H), 8.8 (bs, 1H), 7.87 (bs, 2H), 7.74 (bs,2H), 7.43 (dd, 1H), 7.40 (bs, 1H), 7.33 (t, 1H), 7.06 (d, 1H), 6.98 (bs,1H), 6.3 (bs, 1H), 5.14 (dd, 1H), 3.84 (t, 2H), 3.78 (bt, 2H), 3.7-3.0(m, 10H), 2.84 (bs, 3H).

Example 931-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,5-pyrrolidinedione(E93)

Dihydro-2,5-furandione (2 eq) was added to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6)(1 eq)in toluene/pyridine (3:2) at room temperature under an inert atmosphere.The solution was stirred for 30 min at room temperature, then irradiatedin a microwave reactor (PersonalChemistry Emrys™ Optimiser, 300W, 170°C., 20 min, 4 cycles), diluted with dichloromethane and washed with asaturated aqueous solution of NH₄Cl and brine and then dried overNa₂SO₄. The solution was concentrated under reduced pressure. The crudematerial was purified on SPE cartridge (Silica) eluting with a gradientfrom dichloromethane/MeOH 99/1 to dichloromethane/MeOH 98/2 affordingthe final compound in 76% yield.

The free base was converted into its dihydrochloride salt by dissolvingthe compound in Et₂O and MeOH and adding an 1M ethereal solution of HCl(2.1 eq) dropwise. A yellow solid precipitated and the suspension wasstirred for 15 min. The solvent was removed under reduced pressureaffording a crude material which was triturated with Et₂O to give thetitle compound.

MS: (ES) m/z: 429 [MH⁺]. C₂₆H₂₈N₄O₂ requires 428. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 11.1 (bs, 1H), 8.91 (bs, 1H), 7.94 (bs, 2H), 7.81 (bs,1H), 7.49 (t, 1H), 7.44 (bs, 1H), 7.37 (d, 1H), 7.22 (s, 1H), 7.18 (d,1H), 3.73 (bm, 2H), 3.59 (bm, 2H), 3.48 (bm, 4H), 3.33 (m, 2H), 3.19 (m,2H), 2.89 (bs, 3H), 2.80 (bs, 4H).

Example 94N-(3-{2-[4-(7-Chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamidedihydrochloride (E94)

The title compound was prepared in 65% yield according to the generalprocedure for the preparation of the amides (Method B) starting from3-{2-[4-(7-Chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D18) and acetyl chloride.

MS: (ES) m/z: 423 [MH⁺]. C₂₄H₂₇ClN₄O requires 422. ¹H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.68 (bs, 1H), 9.99 (s, 1H), 8.53 (bs, 1H), 7.80 (s,1H), 7.65 (s, 1H), 7.58 (d, 1H), 7.37 (d, 1H), 7.28 (m, 2H), 6.97 (d,1H), 4-3.2 (bm, 10H), 3.07 (dd, 1H), 2.74 (s, 3H), 2.04 (s, 3H).

Example 95N-(3-{2-[4-(7-chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)methanesulfonamidedihydrochloride (E95)

The title compound was prepared in 65% yield using a similar procedureto example E43 starting from3-{2-[4-(7-Chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D18) and methanesulfonyl chloride.

MS: (ES) m/z: 459 [MH⁺]. C₂₃H₂₇ClN₄O₂S .2HCl requires 458. ¹H-NMR (400MHz, d₆-DMSO) δ(ppm): 10.69 (bs, 1H), 9.80 (s, 1H), 8.53 (d, 1H), 7.79(s, 1H), 7.58 (d, 1H), 7.33 (t, 1H), 7.27 (s, 1H), 7.15 (d, 1H), .7.11(d, 1H), 7.05 (d, 1H), 3.7-3.2 (bm, 10H), 3.09 (dd, 2H), 3.01 (s, 3H),2.73 (s, 3H).

Example 96N¹,N¹-Dimethyl-N²-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)glycinamidedihydrochloride (E96)

Diisopropylethylamine (2 eq), Nal (2 eq) and2-chloro-N,N-dimethylacetamide (1.1 eq) were added sequentially to astirred solution of3-{2-[4-(7-chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (1eq) in dimethylformamide at room temperature under an inert atmosphere.The solution was stirred for 2 hrs at 60° C., then the solvent wasremoved by means of an SCX cartridge. The crude material was purified onSPE cartridge (Silica) eluting with a gradient of dichloromethane/MeOH99/1 to dichloromethane/MeOH 98/2 affording the final compound in 38%yield.

The free base was converted into its dihydrochloride salt by dissolvingthe compound in Et₂O and MeOH and adding an 1M ethereal solution of HCl(2.1 eq) dropwise. A yellow solid precipitated and the suspension wasstirred for 15 min. The solvent was removed under reduced pressureaffording a crude material which was triturated with Et₂O to give thetitle compound.

MS: (ES) m/z: 466 [MH⁺]. C₂₆H₃₂ClN₅O requires 465. ¹H-NMR (500 MHz,CD₃OD) δ(ppm): 9.19 (d, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.62 (d, 1H),7.45 (t, 1H), 7.32 (bs, 1H), 7.25 (bd, 1H), 7.19 (bd, 1H), 4.37 (bs,2H), 3.85 (bd, 2H), 3.65 (bm, 4H), 3.60 (dd, 2H), 3.45 (bt, 2H), 3.25(dd, 2H), 3.06 (s, 3H), 3.02 (s, 3H), 3.01 (s, 3H).

Example 972-Methyl-5-(4-{[3-(1H-pyrazol-1-yl)phenyl]acetyl}-1-piperazinyl)quinoline(E97)

EDC.HCl (1.5 eq), HOBt (2 eq) and 2-methyl-5-(1-piperazinyl)quinoline(D3)(1 eq) were added sequentially to a stirred solution of[3-(1H-pyrazol-1-yl)phenyl]acetic acid (D19)(1.1 eq) indimethylformamide at room temperature under an inert atmosphere.

The solvent was removed by means of an SCX cartridge. The crude materialwas purified on SPE cartridge (Silica) eluting with a gradient fromdichloromethane/MeOH 99/1 to dichloromethane/MeOH 98/2 affording thetitle compound in 74% yield.

MS: (ES) m/z: 412 [MH⁺]. C₂₅H₂₅N₅O requires 411. ¹H-NMR (400 MHz, CDCl₃)δ(ppm): 8.36 (d, 1H), 7.93 (d, 1H), 7.75 (d, 1H), 7.71 (s, 1H), 7.69 (s,1H), 7.58 (d, 1H), 7.55 (t, 1H), 7.42 (t, 1H), 7.25 (m, 2H), 7.00 (d,1H), 6.46 (s, 1H), 3.87 (s, 2H), 4.0-3.7 (m, 4H), 3.1-2.9 (m, 4H), 2.72(s, 3H).

Example 982-Methyl-5-(4-{2-[3-(1H-pyrazol-1-yl)phenyl]ethyl}-1-piperazinyl)quinoline(E98)

A 1M tetrahydrofuran solution of borane-tetrahydrofuran complex (3 eq)was added to a stirred solution of2-methyl-5-(4-{[3-(1H-pyrazol-1-yl)phenyl]acetyl}-1-piperazinyl)quinoline(E97)(1 eq) in tetrahydrofuran at room temperature under an inertatmosphere. The solution was heated to 60° C. for 3 hrs. An aqueous 3Nsolution of HCl was added and the solution was stirred at roomtemperature for 12 hrs. The solvent was removed under reduced pressure.The crude material was purified by SCX cartridge affording the titlecompound in 52% yield.

MS: (ES) m/z: 398 [MH⁺]. C₂₅H₂₇N₅ requires 397. ¹H-NMR (300 MHz, CDCl₃)δ(ppm): 8.35 (d, 1H), 7.90 (d, 1H), 7.70 (d, 1H), 7.70 (s, 1H), 7.65 (t,1H), 7.60 (t, 1H), 7.50 (dd, 1H), 7.35 (t, 1H), 7.25 (d, 1H), 7.15 (d,1H), 7.05 (d, 1H), 6.45 (t, 1H), 3.20 (m, 4H), 3.0-2.7 (m, 8), 2.70 (s,3H).

Example 99 N-(3-{2-[4-(6-Fluoro-2-methyl-5-quinolinyl)-1piperazinyl]ethyl}phenyl)acetamide (E99) 1,1-dimethylethyl4-(6-fluoro-2-methyl-5-quinolinyl)-1-piperazinecarboxylate

A mixture of 5-bromo-6-fluoro-2-methylquinoline (Chem. Pharm. Bull.,1989, 37(8), 2103-8, 0.285 g), 1,1-dimethylethyl 1-piperazinecarboxylate(0.265 g, 1.2 equiv.), Pd(OA)2 (15 mol %, 0.04 g),bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 30 mol %, 0.221 g),cesium carbonate (1.5 equiv. 0.580 g) and toluene (3.5 mL) were stirredat 120° C. for 20 h in a sealed tube. The mixture was cooled to roomtemperature and partitioned between ethyl acetate and brine. The organiclayer was dried over sodium sulfate, filtered and concentrated. Thiscrude product was purified by flash chromatography [SiO₂; DCM-MeOH(99:1)→(90:10)] to afford the title compound as colourless solid (0.270g, 65% yield).

MS: (ES/+) m/z: 346 [MH⁺]. C₁₉H₂₄FN₃O₂ requires 345. 1H-NMR (300 MHz,CDCl₃) □(ppm): 8.55 (d, 1H), 7.80 (dd, 1H), 7.40-7.2 (m, 2H), 3.5-2.9(m, 8H), 2.65 (s, 3H), 1.5 (s, 9H).

6-Fluoro-2-methyl-5-(1-piperazinyl)quinoline

A solution of hydrogen chloride in dioxane (4M, 4 mL) was added to asolution of1,1-dimethylethyl-4-(6-fluoro-2-methyl-5-quinolinyl)-1-piperazinecarboxylate(0.178 g) in dioxane (4 mL) at 0° C. The resulting mixture was warmed toroom temperature and stirred for 15 h. The mixture was concentrated invacuo and partitioned between aqueous sodium hydroxide solution and DCM.The combined organic phases were washed with brine, dried over sodiumsulfate and concentrated to afford the title compound (198 mg, 100%yield).

MS: (ES/+) m/z: 246 [MH⁺]. C₁₄H₁₆FN₃ requires 245. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.55 (d, 1H), 7.80 (dd, 1H), 7.40-7.2 (m, 2H), 3.5-2.9(m, 8H), 2.65 (s, 3H).

6-Fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline

N,N-Diisopropylethylamine (0.15 mL; 3 eq) was added to a solution of2-methyl-5-(1-piperazinyl)-6-fluoro quinoline (0.075 g; 1 eq) and2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.08; 1.1 eq) indimethylformamide (3.0 mL). The reaction mixture was heated to 100° C.for 10 hours. The dark solution was concentrated under reduced pressure,diluted with water (3 mL) and brine (1 mL) and extracted into ethylacetate (3×3 mL). The organic layers were combined, dried over sodiumsulfate and concentrated under reduced pressure. The crude was purifiedby flash chromatography on silica gel, eluting with a gradient fromdichloromethane to dichloromethane-methanol (98:2) affording the titlecompound in 42% yield (0.05 g).

MS; (ES) m/z: 395.2 [MH]⁺. C₂₂H₂₃FN₄O₂ requires 394.

3-{2-[4-(6-Fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline

A solution of6-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline(0.05 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension ofiron powder (0.05 g; 7 eq) and ammonium chloride (0.05 g; 7 eq) in water(3 mL). The reactants were heated at reflux for 8 hours, with additionalamounts of iron powder (total 0.05 g; 7 eq) and ammonium chloride (0.05g; 7 eq) added in 3 portions during the reaction. The reaction mixturewas cooled to room temperature and filtered using a Millipore filter.The filtrate was concentrated under reduced pressure, diluted with water(5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2mL) and extracted into ethyl acetate (3×5 mL). The combined organiclayers were dried over sodium sulfate and concentrated under reducedpressure to give the title compound in 91% yield (0.04 g).

MS; (ES) m/z: 365 [MH]⁺. C₂₂H₂₆N₄ requires 346. 1H-NMR (300 MHz,d₆-DMSO) □(ppm): 8.50 (d, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.60 (d, 1H),6.80 (t, 1H), 6.65 (bs, 1H), 6.60 (m, 2H), 3.3-2.8 (bm, 12H), 3.15 (t,4H), 2.75 (s, 3H).

N-(3-{2-[4-(6-Fluoro-2-methyl-5-quinolinyl)-1piperazinyl]ethyl}phenyl)acetamide (E99)

The title compound was prepared in 78% yield according to Method B forthe preparation of amides starting from3-{2-[4-(6-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline andacetyl chloride.

MS: (ES) m/z: 407.5 [MH⁺]. C₂₄H₂₇FN₄O requires 406. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 9.67 (bs, 1H), 8.50 (d, 1H), 7.73 (dd, 1H), 7.53 (dd,1H), 7.44 (d, 1H), 7.46 (bs, 1H), 7.39 (d, 1H), 7.19 (t, 1H), 6.93 (d,1H), 3.17 (bs, 4H), 2.8-2.5 (bm, 8H), 2.64 (s, 3H), 2.03 (s, 3H).

Example 100 N-(3-{2-[4-(8-Fluoro-2-methyl-5-quinolinyl)-1piperazinyl]ethyl}phenyl)acetamide (E100) 8-Fluoro-2-Methyl-5-quinolinyltrifluoromethanesulfonate

A solution of 8-fluoro-2-methyl-quinolin-5-ol (WO/2002034754) (103 mg,0.58 mmol) and pyridine (1 mL) in dichloromethane (4 mL) was cooled to0° C. and trifluoromethanesulfonic anhydride (144 μL) was added. Thereaction mixture was stirred under an inert atmosphere at roomtemperature for 1 h, then poured into water and extracted into ethylacetate. The organic layers were combined, dried (sodium sulfate) andconcentrated under reduced pressure. The crude was purified by flashchromatography on silica gel, eluting with ethyl acetate-cyclohexane(4:6) affording the title compound (134 mg, 74% yield). 1H-NMR (300 MHz,d6-DMSO) δ(ppm): 8.31 (m, 1H), 7.85 (m, 1H), 7.60 (m, 2H), 2.82 (s, 3H).

4-(8-Fluoro-2-methyl-5-quinolin-5-yl)-piperazine-1-carboxylic acidtert-butyl ester

1,1-Dimethylethyl 1-piperazinecarboxylate (96 mg, 0.52 mmol), cesiumcarbonate (211 mg, 0.65 mmol), palladium acetate (14 mg, 0.06 mmol) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (80 mg, 0.13 mmol) wereadded to a solution of 8-fluoro-2-methyl-5-quinolinyltrifluoromethanesulfonate (134 mg, 0.43 mmol) in toluene (1.5 mL) underan inert atmosphere. The reaction mixture was stirred at reflux for 6hours. The reaction was then cooled to room temperature and quenchedusing a saturated aqueous solution of ammonium chloride and extractedinto ethyl acetate. The organic layers were combined, dried (sodiumsulfate) and concentrated under reduced pressure. The crude was purifiedby flash chromatography on silica gel, eluting with ethylacetate-cyclohexane (1:9) affording the title compound (50 mg, 34%yield). MS; (ES) m/z: 346 [MH⁺]. C₁₉H₁₄FN₃O₂ requires 345.

8-Fluoro-2-Methyl-5-piperazin-1-yl-quinoline

4-(8-Fluoro-2-Methyl-5-quinolin-5-yl)-piperazine-1-carboxylic acidtert-butyl ester (50 mg, 0.14 mmol) was dissolved in 1,4-dioxane (0.5mL) and HCl (2.5 mL of a 4N solution in dioxane) was added understirring. After stirring for 4 hours, the solvent was evaporated toyield a white solid that was dissolved in water, basified with solidsodium hydroxide (pH>10) and extracted with dichloromethane. The organiclayer was dried (sodium sulfate) and then evaporated under reducedpressure to afford the title compound (50 mg, 70% yield).

MS; (ES) m/z: 246 [MH⁺]. C₁₄H₁₆FN₃ requires 245.

8-Fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline

N,N-Diisopropylethylamine (0.25 mL; 3 eq) was added to a solution of2-methyl-5-(1-piperazinyl)-8-fluoro quinoline (0.170 g; 1 eq) and2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.17 g; 1 eq) indimethylformamide (4.0 mL). The reaction mixture was heated to 100° C.for 10 hours. The dark solution was cooled to room temperature andconcentrated under reduced pressure. The residue was diluted with water(3 mL) and brine (1 mL) and extracted into ethyl acetate (3×3 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The crude was purified by flash chromatographyon silica gel, eluting with a gradient from dichloromethane todichloromethane-methanol (98:2) affording the title compound in 46%yield (0.126 g).

MS; (ES) m/z: 395.5 [MH]⁺. C₂₂H₂₃FN₄O₂ requires 394. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.38 (d, 1H), 8.10 (s, 1H), 8.05 (m, 1H), 7.56 (m, 1H),7.50 (t, 1H), 7.35 (m, 2H), 6.95 (m, 1H), 3.15 (m, 4H), 2.95 (m, 2H),2.80-2.70 (m, 7H), 2.75 (s, 3H).

3-{2-[4-(8-Fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline

A solution of8-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline(0.126 g; 1 eq) in methanol (4 mL) was added dropwise to a suspension ofiron powder (0.125 g; 7 eq) and ammonium chloride (0.119 g; 7 eq) inwater (4 mL). The reactants were heated at reflux for 8 hours, withadditional amounts of iron powder (total 0.125 g; 7 eq) and ammoniumchloride (0.119 g; 7 eq) added in 3 portions during the reaction. Thereaction mixture was cooled to room temperature and filtered using aMillipore filter. The filtrate was concentrated under reduced pressure,diluted with water (5 mL) and a saturated aqueous solution of sodiumhydrogen carbonate (2 mL) and extracted into ethyl acetate (3×5 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated under reduced pressure to give the title compound in 77%yield (0.090 g).

MS; (ES) m/z: 365.3 [MH]⁺. C₂₂H₂₅FN₄ requires 364. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.36 (d, 1H), 7.31 (m, 1H), 7.05 (t, 1H), 7.00 (m, 1H),6.70 (m, 1H), 6.55 (m, 2H), 3.70 (bs, 2H), 3.15 (bm, 4H), 2.80-2.70 (m,7 H), 2.75 (s, 3H).

N-(3-{2-[4-(8-Fluoro-2-methyl-5-quinolinyl)-1piperazinyl]ethyl}phenyl)acetamide(E100)

The title compound was prepared in 26% yield according to the generalprocedure for the preparation of amides (Method B) starting from3-{2-[4-(8-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline andacetyl chloride.

MS: (ES) m/z: 407.5 [MH⁺]. C₂₄H₂₇FN₄O requires 406. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 10.74 (bs, 1H), 10.00 (s, 1H), 8.46 (dd, 1H), 7.63 (bs,1H), 7.55 (d, 1H), 7.49 (dd, 1H), 7.39 (d, 1H), 7.23 (t, 1H), 7.18 (dd,1H), 6.97 (d, 1H), 3.69 (bd, 2H), 3.44 (m, 2H), 3.83 (m, 2H), 3.21 (m,2H), 3.32 (m, 2H), 3.08 (m, 2H), 2.69 (s, 3H), 2.04 (s, 3H).

Example 101 O-Methyl(2-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)thiocarbamatedihydrochloride (E101)

The title compound was prepared in 55% yield according to the generalprocedure for the preparation of carbamates (Method D) starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) andphenyl chlorothionoformate. The crude obtained was hydrolysed with 1Naqueous NaOH in THF/MeOH 4:1 and purified according to the generalprocedure indicated above.

MS: (ES/+) m/z: 421 [MH⁺] C.₂₅H₃₀N₄O₂ requires 420. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 11 (2H, s), 8.90 (1H, bs), 7.94 (2H, bs), 7.81 (1H,bs), 7.43 (1H, m), 7.33 (2H, t), 7.19 (1H, d), 4.0-3.2 (15H, m), 2.96(3H, s).

Example 102N-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide(E102)N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]acetyl}phenyl)acetamide

To a stirred solution of 2-methyl-5-(1-piperazinyl)quinoline (D6, 0.14g,1 eq) in dry DMF (5 mL) were added potassium carbonate (0.11 g, 1.2eq) and a solution of N-[3-(2-chloroacetyl)phenyl]acetamide (J. Chem.Soc., 1949, 552, 553, 0.17 g, 1.2 eq) in DMF (3 mL) under an inertatmosphere. The reaction was stirred for 1.5 hrs. The mixture wasdiluted with water (8 mL) and extracted with DCM (3×15 mL). The organicphase was washed with brine (25 mL), dried over sodium sulfate and thesolvent was removed under reduced pressure. The crude material waspurified on SPE cartridge (Silica) using as eluant DCM-methanol (95:5),affording the title compound in 42% yield (0.104 g).

MS; (ES) m/z: 403.2 [MH⁺]. C₂₄H₂₆N₄O₂ requires 402. 1H-NMR (500 MHz,CDCl₃) δ(ppm): 8.40 (d, 1H), 8.13 (s, 1H), 7.84 (d, 1H), 7.79 (d, 1H),7.73 (d, 1H), 7.59 (t, 2H), 7.45 (t, 1H), 7.39 (bs, 1H), 7.27 (d, 1 H),7.09 (d, 1 H), 3.95 (s, 2H), 3.18 (t, 4H), 2.91 (bs, 4H), 2.74 (s, 3H),2.23 (s, 3H).

N-(3-{1-Hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide(E102)

Sodium borohydride (0.015 g, 1.6 eq) was added to a stirred solution ofN-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]acetyl}phenyl)acetamide(0.102 g, 1 eq) in dry DCM (2 mL) cooled to 0° C. under an inertatmosphere. The reaction was warmed to room temperature and stirred for18 hours. The mixture was diluted with DCM (10 mL) and washed with water(2×10 mL). The organic phase was dried over sodium sulfate and thesolvent was removed under reduced pressure. The crude material waspurified on SPE cartridge (Silica) using as eluant DCM-methanol (97:3),affording the title compound in 42% yield (0.104 g).

MS; (ES) m/z: 405.3 [MH⁺]. C₂₄H₂₈N₄O₂ requires 404. 1H-NMR (500 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.60 (s+d, 2H), 7.40 (d, 1H),7.30 (t, 1H), 7.30-7.2 (d+s, 2H), 7.20-7.10 (t, 1H), 7.05 (d, 1 H), 4.8(dd, 1 H), 3.10 (bs, 4H), 3.0 (bs, 2H), 2.7 (m, 4H), 2.7 (s, 3H), 2.1(s, 3H).

Example 103N-(5-Chloro-1,3-benzoxazol-2-yl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)urea(E103)

Triethylamine (6 eq) and then triphosgene (0.5 eq) were addedportionwise to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq)in dichloromethane at 0° C. under an inert atmosphere. The reaction wasstirred for 1 h. To the mixture were added acetonitrile,diisopropylethylamine (2 eq) and 5-chloro-1,3-benzoxazol-2-amine (1.1eq). The reaction was stirred for 16 h.

The mixture was extracted with dichloromethane and washed with saturatedaqueous sodium hydrogencarbonate solution and brine, dried over sodiumsulfate and the solvent was removed under reduced pressure. The crudematerial was purified by chromatography on SPE cartridge (Silica), usingas eluent a gradient from dichloromethane-MeOH 99:1 todichloromethane-MeOH 98:2, affording the title compound (yield 47%).

1H-NMR (400 MHz, CDC1₃) δ(ppm): 8.35(1H, d), 7.8 (1H, d), 7.6 (1H, t),7.55 (2H, m), 7.45 (1H, d), 7.35-7.20 (4H, m), 7.15 (1H, d), 7.05 (1H,d), 3.35 (4H, m), 3.2 (4H, m), 3.1 (4H, s), 2.75 (3H, s).

Example 104 (R or S)N-(3-{1-hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamidedihydrochloride (E104)

RacemicN-(3-{1-hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide(E40) was separated preparative chiral HPLC using a Daicel Chiralcel OJcolumn and a mixture of n-hexane and ethanol (75:25) as eluent to affordthe title compound as the first-eluting enantiomer.

MS: (ES/+) m/z: 502 [MH⁺]. C₂₈H₃₁N₅O₂S requires 501.65. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.18 (2H, br s), 8.85 (1H, br s), 7.89 (3H, s), 7.77(1H, br s), 7.53 (1H, d), 7.37 (2H, m), 7.18 (1H, d), 6.36 (1H, br s),5.17 (1H, dd), 3.80-3.20 (10H, m), 2.85 (3H, s), 2.64 (3H, s), 2.53 (3H,s).

Example 105 (S or R)N-(3-{1-hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamidedihydrochloride (E105)

RacemicN-(3-{1-hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamidewas separated using preparative chiral HPLC using a Daicel Chiralcel OJcolumn and a mixture of n-hexane and ethanol (75:25) as eluent to affordthe title compound as the second-eluting enantiomer.

MS: (ES/+) m/z: 502 [MH⁺]. C₂₈H₃₁N₅O₂S requires 501.65. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.18 (2H, br s), 8.85 (1H, br s), 7.89 (3H, s), 7.77(1H, br s), 7.53 (1H, d), 7.37 (2H, m), 7.18 (1H, d), 6.36 (1H, br s),5.17 (1H, dd), 3.80-3.20 (10H, m), 2.85 (3H, s), 2.64 (3H, s), 2.53 (3H,s).

General Procedure for the Preparation of Imides Starting From3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6): MethodI

A solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6), thephthalic anhydride (2 eq) in dry pyridine and dry toluene (2/3 ratio)was heated in a microwave apparatus at 160° C. for 20 minutes under aninert atmosphere. The mixture was then cooled to room temperature,diluted with DCM and washed with saturated aqueous ammonium chloridesolution, dried over sodium sulfate and the solvent was removed underreduced pressure. The crude material was purified by chromatography,using a SPE cartridge (Silica) and gradient elution fromdichloromethane/MeOH 99/1 to dichloromethane-MeOH 95:5, affording thefinal compounds (yields ranged from 55 to 94%).

Example 1062-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione(E106)

Prepared from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and2-benzofuran-1,3-dione according to Method I.

MS; (ES) m/z: 477.3 [MH]⁺. C₃₀H₂₈N₄O₂ requires 476. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.37 (d, 1H), 7.94 (m, 2H), 7.79 (m, 2H), 7.70 (d, 1H),7.56 (t, 1H), 7.43 (t, 1H), 7.31-7.22 (m, 4H), 7.06 (d, 1H), 3.10 (m,4H), 2.90 (m, 2H), 2.80 (m, 6H), 2.70 (s, 3H).

Example 1072-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,3-dihydro-1H-isoindol-1-one(E107)

A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was addedslowly to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 1 eq)in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for15 min then a solution of phthalide (1 eq) in dichloromethane was addeddropwise. The solution was stirred for 2 h at 0° C. then partitionedbetween saturated aqueous ammonium chloride solution and ethyl acetate.The organic phase was dried over sodium sulfate and the solution wasconcentrated under reduced pressure. The crude2-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamidewas dissolved in dichloromethane then N,N-diisopropylethylamine (1 eq.)and methanesulfonyl chloride (1 eq.) were added successively. Thereaction mixture was stirred for 2 hours at room temperature thenpartitioned between saturated aqueous ammonium chloride solution anddichloromethane. The organic phase was dried over sodium sulfate andconcentrated under reduced pressure. The residue was purified bychromatography (SPE cartridge, Silica) eluting with a gradient fromdichloromethane-methanol (100:2) to (98:2) affording the title compound(yield 45%).

MS; (ES) m/z: 463.3 [MH]⁺. C₃₀H₃₀N₄O requires 462. 1H-NMR (400 MHz,CDCl₃) δ(ppm): 8.41 (d, 1H), 8.01 (d, 1H), 7.73 (d, 1H), 7.62-7.48 (m,3H), 7.44 (d, 1H), 7.34-7.22 (m, 2H), 7.17 (m, 2H), 7.09 (d, 1 H), 7.02(d, 1H), 5.42 (s, 2H), 3.17 (t, 4H), 2.94-2.74 (m, 8H), 2.74 (s, 3H).

Example 1084-fluoro-2-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione (E108)

Prepared from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and4-fluoro-2-benzofuran-1,3-dione according to Method I.

MS; (ES) m/z: 495.3 [MH]⁺. C₃₀H₂₇FN₄ O₂ requires 494. ¹H-NMR (400 MHz,CDCl₃) δ(ppm): 8.42 (d, 1H), 7.84-7.82 (m, 2H), 7.75 (d, 1H), 7.62 (t,1H), 7.51-7.47 (m, 2H), 7.35-7.28 (m, 4H), 7.12 (d, 1H), 3.19 (bs, 4H),3.10-2.70 (m, 8H), 2.76 (s, 3H).

Example 1095,6-dichloro-2-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione

Prepared from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and5,6-dichloro-2-benzofuran-1,3-dione according to Method I.

MS; (ES) m/z: 545.2 [MH]⁺. C₃₀H₂₆Cl₂N₄O₂ requires 544. ¹H-NMR (400 MHz,CDCl₃) δ(ppm): 8.42 (d, 1H), 8.07 (s, 2H), 7.75 (d, 1H), 7.62 (t, 1H),7.49 (t, 1H), 7.36-7.28 (m, 4H), 7.11 (d, 1H), 3.18 (bs, 4H), 3.10-2.70(m, 6 H), 2.99 (t, 2H), 2.76 (s, 3H).

Example 1105-methyl-2-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1H-isoindole-1,3(2H)-dione(E110)

Prepared from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and5-methyl-2-benzofuran-1,3-dione according to Method I.

MS; (ES) m/z: 491.3 [MH]⁺. C₃₁H₃₀N₄O₂ requires 490. 1H-NMR (400 MHz,CDCl₃) δ(ppm): 8.42 (d, 1H), 7.87 (d, 1H), 7.79 (s, 1H), 7.76 (d, 1H),7.64-7.60 (m, 2H), 7.48 (t, 1H), 7.35-7.29 (m, 4H), 7.13 (d, 1H), 3.21(bs, 4 H), 3.10-2.80 (m, 8H), 2.77 (s, 3H), 2.59 (s, 3H).

Example 1114-(Methoxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)benzamide(E111) 5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline(D20)

A solution of zinc(ll)chloride (0.5 M, THF, 0.5 eq., 234 uL) was addedto a stirred solution of 1-(3-bromophenyl)-2-propanone (50 mg) and2-methyl-5-(1-piperazinyl)quinoline (D3) (2.0 eq., 107 mg) in methanol(1 ml). The mixture was stirred 10 minutes then a solution of sodiumcyanoborohydride (1M, THF, 1.0 eq., 234 uL) was added. The resultingwhite mixture was stirred at room temperature until hplc showed thecomplete disappearance of starting material. The mixture wasconcentrated under reduced pressure, diluted with aqueous sodiumhydroxide solution (1M), and extracted with DCM. The combined organicphases were washed with brine, dried over sodium sulfate andconcentrated. The crude was purified by chromatography using a SPEcartridge (SiO₂) with DCM-methanol (98:2) as eluent to afford the titlecompound (50 mg, 50% yield).

MS: (ES/+) m/z: 424, 426 [MH⁺]. C₂₃H₂₆BrN₃ requires 423, 425. 1H-NMR(300 MHz, CDC1₃) δ(ppm): 8.30 (d, 1H), 7.80(d, 1H), 7.70 (t, 1H),7.50-7.30 (m, 6H), 3.25-2.95 (m, 10H), 2.80 (s, 3H), 2.55 (m, 1H), 1.15(d, 3H).

4-(Methoxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)benzamide(E111)

The title compound was prepared in 21% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and 4-methoxybenzamide.

MS: (ES/+) m/z: 495 [MH⁺]. C₃₁H₃₄N₄O₂ requires 494. 1H-NMR (400 MHz,DMSO) δ(ppm): 10.63 (br s, 1H), 10.16 (s, 1H), 8.91 (br s, 1H), 7.99 (d,2H), 7.86 (m, 3H), 7.74 (br s, 1H), 7.61 (d, 1H), 7.41 (br s, 1H), 7.37(t, 1H), 7.08 (d, 3H), 3.86 (s, 3H), 3.66 (br s, 4H), 3.80-2.70 (m,10H), 1.28 (d, 3H).

Example 1122-Fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)benzamide(E112)

The title compound was prepared in 40% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and 2-fluorobenzamide.

MS: (ES/+) m/z: 483 [MH⁺]. C₃₀H₃₁FN₄0 requires 482. 1H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.85 (br s, 1H), 10.48 (s, 1H), 8.97 (br s, 1H), 7.92(br s, 2H), 7.83 (s, 1H), 7.78 (br s, 1H), 7.68 (td, 1H), 7.61 (qd, 1H),7.55 (d, 1H), 7.43 (br s, 1H), 7.40-7.34 (m, 3H), 7.11 (d, 1H), 4.0-2.7(m, 11H), 2.88 (s, 3H), 1.28 (d, 3H).

Example 1133-Fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)benzamide(E113)

The title compound was prepared in 55% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and 3-fluorobenzamide.

MS: (ES/+) m/z: 483 [MH⁺]. C₃₀H₃₁FN₄0 requires 482. 1H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.39 (s, 1H), 10.30 (br s, 1H), 8.77 (br s, 1H),7.90-7.82 (m, 5H), 7.70-7.52 (m, 3H), 7.48 (td, 1H), 7.40-7.35 (m, 2H),7.12 (d, 1H), 3.8-2.7 (m, 14H), 1.28 (d, 3H).

Example 1143-(Methoxy)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)benzamide(E114)

The title compound was prepared in 35% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and 3-methoxybenzamide.

MS: (ES/+) m/z: 495 [MH⁺]. C₃₁H₃₄N₄O₂ requires 494. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.7 (br s, 1H), 10.29 (s, 1H), 8.90 (Br s, 1 H), 7.89(br s, 2H), 7.86 (s, 1H), 7.75 (br s, 1H), 7.62 (d, 1H), 7.57 (d, 1H),7.51 (t, 1H), 7.45 (br s, 1H), 7.38 (t, 1H), 7.19 (dd, 1H), 7.11 (dd,1H), 3.86 (s, 3H), 3.75 (m, 1H), 3.66-2.86 (m, 14H), 2.78 (t, 1H), 1.28(d, 3H).

Example 115N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)acetamide(E115)

The title compound was prepared in 64% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and acetamide.

MS: (ES/+) m/z: 403 [MH⁺]. C₂₅H₃₀N₄O requires 402. 1H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.74 (br s, 1H), 10.01 (s, 1H), 8.93 (br s, 1H), 7.90(br s, 2H), 7.76 (br s, 1H), 7.65 (s, 1H), 7.41 (br d, 2H), 7.31 (t,1H), 7.02 (d, 1H), 3.80-2.73 (m, 11H), 2.87 (s, 3H), 2.06 (s, 3H), 1.24(d, 3H).

Example 1161-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-3-phenyl-2-imidazolidinone(E116)

The title compound was prepared in 55% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and 1-phenyl-2-imidazolidinone.

MS: (ES/+) m/z: 506 [MH⁺]. C₃₂H₃₅N₅O requires 505. 1H-NMR (400 MHz,DMSO) δ(ppm): 10.4 (br s, 1H), 8.80 (br s, 1H), 7.83 (br s, 2H), 7.71(s, 1H), 7.66 (d, 1H), 7.70-7.60 (m, 1H), 7.51 (br d, 1H), 7.40 (m, 4H),7.10-7.05 (m, 2H), 4.01 (br s, 4H), 3.78 (br m, 1H), 3.66 (br m, 4H),3.5 (br m, 5H), 2.87 (br m, 4H), 1.24 (d, 3H).

Example 1173-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-one(E117)

The title compound was prepared in 73% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and 2-oxazolidone. MS: (ES/+) m/z: 431 [MH⁺]. C₂₆H₃₀N₄O₂ requires 430.1H-NMR (400 MHz, d₆-DMSO) δ(ppm): 10.6 (br s, 1H), 8.90 (br s, 1H), 7.87(br s, 2H), 7.73 (s, 1H), 7.61 (s, 1H), 7.46 (d, 1H), 7.42 (t, 1H), 7.40(br s, 1H), 7.12 (d, 1H), 4.47 (t, 2H), 4.10 (2H), 3.77 (br m, 1H), 3.65(br s, 4H), 3.50-3.40 (br m, 5H), 2.84 (br s, 4H), 2.80 (m, 1H), 1.25(d, 3H).

Example 118N-(3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide(E118) Methyl (3-nitrophenyl)acetate

Trimethylsilyl chloride (5.6 mL, 2.0 equiv.) was added to a stirredsolution of (3-nitrophenyl)acetic acid (4.0 g) in methanol (60 ml). Theresulting solution was stirred at room temperature for 18 hours, thenconcentrated at reduced pressure and partitioned between DCM and aqueoussodium hydrogencarbonate solution. The organic phase was dried oversodium sulfate, filtered and concentrated under vacuum to give the titlecompound as a colourless liquid (4.2 g, 100%).

1H-NMR (300 MHz, CDCl₃) δ(ppm): 8.15 (s, 1H), 8.07 (d, 1H), 7.60 (d,1H), 7.47 (t, 1H), 3.85 (s, 2H), 3.80 (s, 3H).

Methyl 2-(3-nitrophenyl)propanoate

A solution of lithium hexamethyldisilazide (1M, hexane, 1.0 eq., 21.5ml) was added dropwise to a stirred solution of methyl(3-nitrophenyl)acetate (4.2 g) in THF (30 ml) at −30° C. The mixture waswarmed to 0° C. and re-cooled to −30° C. then iodomethane (1.0 equiv.,3.0 g.) was added. The solution was warmed to room temperature andpoured into aqueous ammonium chloride solution and extracted with ethylacetate. The combined organic phases were washed with brine, dried oversodium sulfate and concentrated. The crude was purified usingchromatography (SiO₂, SPE) using cyclohexane/ethyl acetate (80/20) aseluent to afford the title compound as yellow liquid (1.50 g, 30%yield).

11H-NMR (300 MHz, CDCl₃) δ(ppm): 8.15 (s, 1H), 8.10 (d, 1H), 7.60 (d,1H), 7.45 (t, 1H), 3.85 (q, 1H), 3.65 (s, 3H), 1.50 (d, 3H).

2-(3-Nitrophenyl)-1-propanol

A solution of lithium borohydride (2M, THF, 2.0 equiv. 3.4 ml) was addedto a solution of methyl 2-(3-nitrophenyl)propanoate (0.7 g) in THF. Theresulting mixture was stirred for 18 hours then concentrated and pouredinto hydrochloric acid (10%) at 0° C. The mixture was extracted withether. The combined organic phases were dried over sodium sulfate,filtered and concentrated to afford the title compound as yellow oil(0.610 g, 100% yield).

1H-NMR (300 MHz, CDCl₃) δ(ppm): 8.10 (s, 1H), 8.05 (d, 1H), 7.60 (d,1H), 7.45 (t, 1H), 3.75 (d, 2H), 3.05 (sext,1H), 1.30 (d, 3H).

2-(3-Nitrophenyl)propanal

To a stirred suspension of1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane, 1.1 eq., 1.52 g) in DCM (4 mL) was added2-(3-nitrophenyl)-1-propanol (0.610 g). The resulting solution wasstirred for 1 h then poured into water and extracted with DCM. Thecombined organic phases were washed with aqueous sodiumhydrogencarbonate solution and brine, dried over sodium sulfate thenconcentrated to afford a brown solid (1.4 g). This solid was dissolvedin ether and filtered. The filtrate was concentrated under vacuum togive the title compound as yellow liquid (0.57 g, 94% yield).

1H-NMR (300 MHz, CDCl₃) δ(ppm): 9.70 (s, 1H), 8.15 (d, 2H), 8.10 (s,1H), 7.6 (m, 2H), 3.75 (q,1H), 1.50 (d, 3H).

2-Methyl-5-{4-[2-(3-nitrophenyl)propyl]-1-piperazinyl}quinoline

A mixture of 2-(3-nitrophenyl)propanal (1.2 equiv. 50 mg),2-methyl-5-(1-piperazinyl)quinoline (D3) (52 mg) and DCM (2 mL) wasstirred for 1 h. Sodium triacetoxyborohydride (1.2 equiv., 58 mg) wasadded and the resulting mixture was stirred for 18 h. The reactionmixture was concentrated in vacuo and purified using ion-exchangechromatography (SCX-2), eluting with methanol followed by ammonia inmethanol (1M). The basic fractions were concentrated under vacuum andpurified by chromatography (SPE, SiO₂) using DCM-methanol (98:2) aseluent to afford the title compound as yellow liquid (78 mg, 78% yield).

MS; (ES) m/z: 391 [MH]⁺. C₂₃H₂₆N₄O₂ requires 390. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 8.15 (br s, 1H), 8.05 (d, 1H), 7.68 (d,1H), 7.55 (m, 2H), 7.45 (t, 1H), 7.22 (d, 1H), 7.05 (d, 1H), 3.25-3.00(m, 5H), 2.75-2.50 (m, 9H), 1.30 (d, 3H).

3-{1-Methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D21)

A solution of2-methyl-5-{4-[2-(3-nitrophenyl)propyl]-1-piperazinyl}quinoline (70 mg)in methanol (1 mL) was added dropwise to a stirred suspension of ironpowder (3.0 equiv., 30 mg) and ammonium chloride (5.0 equiv., 48 mg) inwater (1 mL). The reactants were heated at reflux for 18 hours. Thereaction mixture was cooled to room temperature then filtered using aMillipore filter. The filtrate was concentrated under reduced pressureand purified using chromatography (SiO₂, SPE) eluting with DCM-methanol(95:5) to afford the title compound (40 mg, 60% yield).

MS; (ES) m/z: 361 [MH]⁺. C₂₃H₂₈N₄ requires 360. 1H-NMR (300 MHz, CDCl₃)δ(ppm): 8.30 (d, 1H), 87.70 (d, 1H), 7.55 (t, 1H), 7.68 (d, 1H),7.25-7.00 (m, 2H), 6.60-6.50 (m, 3H), 3.10-2.50 (m, 14H), 1.30 (d, 3H).

N-(3-{1-Methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide(E118)

The title compound was prepared in 75% yield according to the generalprocedure for the preparation of amides (Method C) starting from3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D21) and acetic acid.

MS: (ES/+) m/z: 403 [MH⁺]. C₂₆H₃₀N₆O₂ requires 402. 1H-NMR (400 MHz,d6-DMSO) δ(ppm): 10.18 (bs, 1H), 10.02 (bs, 1H), 8.78 (bs, 1H), 7.88(bs, 2H), 7.74 (bs, 1H), 7.67 (s. 1H), 7.44 (d, 1H), 7.38 (bs, 1H), 7.32(t, 1H), 7.09 (d, 1H), 3.70-3.20 (m, 1H), 2.85 (bs, 3H), 2.06 (s, 3H),1.35 (d, 3H).

Example 1192-Fluoro-N-(3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide(E119)

The title compound was prepared in 64% yield according to the generalprocedure for the preparation of amides (Method C) starting from3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D21) and 2-fluorobenzoic acid.

MS: (ES/+) m/z: 483 [MH⁺]. C₃₀H₃₁FN₄0 requires 482. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.48 (s, 1H), 10.08 (bs, 1H), 8.76 (bs, 1H), 7.87 (bs,3H), 7.72 (bs, 1H), 7.70-7.50 (m, 3H), 7.40-7.20 (m, 5H), 3.70-3.20 (brm, 10H), 2.84 (br s, 3H), 1.39 (d, 3H).

Example 1202,4-Dimethyl-N-(3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-thiazole-5-carboxamide (E120)

The title compound was prepared in 87% yield according to the generalprocedure for the preparation of amides (Method C) starting from3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline(D21) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.

MS: (ES/+) m/z: 501 [MH⁺]. C₂₉H₃₃N₅0S requires 500. 1H-NMR (400 MHz,DMSO) δ(ppm): 10.63 (br s, 1H), 10.16 (S, 1H), 8.97 (br d, 1H), 8.01 (m,2H), 7.87 (d, 1H), 7.77 (s, 1H), 7.54 (d, 1H), 7.46 (d, 1H), 7.37 (t,1H), 7.18 (d, 1H), 3.5 (m, 11H), 2.95 (s, 3H), 2.68 (s, 3H), 2.56 (s,3H), 1.39 (d, 3H).

Example 1217-Fluoro-2-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,3-dihydro-1H-isoindol-1-one

A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was addedslowly to a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) (1 eq)in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for15 min then a solution of 7-fluoro-2-benzofuran-1(3H)-one (1 eq, Chem.Pharm. Bull., 1985, 33(7), 2809-2820) in DCM was added dropwise. Thesolution was stirred for 2 h at 0° C. then partitioned between saturatedaqueous ammonium chloride solution and ethyl acetate. The organic phasewas dried over sodium sulfate and concentrated under reduced pressure.The crude2-fluoro-6-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamidewas dissolved in DCM and to 0° C. To the stirred solution was addeddropwise thionyl chloride (1 eq.). The reaction mixture was warmed toroom temperature, stirred for 1 hour then partitioned between saturatedaqueous sodium hydrogencarbonate solution and DCM. The organic phase wasdried over sodium sulfate, filtered and the solvent removed underreduced pressure. The crude2-(chloromethyl)-6-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamidethus obtained was dissolved in methanol and cooled to 0° C. To thestirred solution was added sodium methoxide (1.2 eq.) portionwise. Thesolution was warmed to room temperature and stirred for 18 hours. Thesolution was concentrated and partitioned between water anddichloromethane. The organic phase was dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue waspurified by chromatography on SPE cartridge (Silica) eluting withDCM-methanol (96:4) affording the title compound (yield 24%).

The free base could be converted into its dihydrochloride salt bydissolving the compound in dichloromethane and adding a 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure affording a crude material which was triturated with ether. Thefinal compound was then recovered by filtration (yield quantitative).

MS; (ES) m/z: 481.3 [MH]⁺. C₃₀H₂₉FN₄O requires 480. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.4 (vbs, 1H), 8.60 (vbs, 1H), 7.95 (s, 1H), 7.79-7.72(m, 4H), 7.60 (vbs, 1H), 7.53-7.46 (d+t, 2H), 7.34 (t+vbs, 2 H), 7.18(d, 1 H), 5.08 (s, 2H), 3.80-3.10 (m, 12H), 2.77 (s, 3H).

Example 122 (R or S)3-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-one(E122)

3-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-one(E118) was separated using preparative chiral HPLC [Daicel Chiralcel ODcolumn; n-hexane-ethanol (55:45)] to afford the title compound as thefirst-eluting enantiomer.

(ES/+) m/z: 431 [MH⁺]. C₂₆H₃₀N₄O₂ requires 430. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.6 (br s, 1H), 8.90 (br s, 1H), 7.87 (br s, 2H), 7.73(s, 1H), 7.61 (s, 1H), 7.46 (d, 1H), 7.42 (t, 1H), 7.40 (br s, 1H), 7.12(d, 1H), 4.47 (t, 2H), 4.10 (2H), 3.77 (br m, 1H), 3.65 (br s, 4H),3.50-3.40 (br m, 5H), 2.84 (br s, 4H), 2.80 (m, 1H), 1.25 (d, 3H).

Example 123 (S or R)3-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-one(E123)

3-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-one(E118) was separated using preparative chiral HPLC [Daicel Chiralcel ODcolumn; n-hexane-ethanol (55:45)] to afford the title compound as thesecond-eluting enantiomer.

(ES/+) m/z: 431 [MH⁺]. C₂₆H₃₀N₄O₂ requires 430. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.6 (br s, 1H), 8.90 (br s, 1H), 7.87 (br s, 2H), 7.73(s, 1H), 7.61 (s, 1H), 7.46 (d, 1H), 7.42 (t, 1H), 7.40 (br s, 1H), 7.12(d, 1H), 4.47 (t, 2H), 4.10 (2H), 3.77 (br m, 1H), 3.65 (br s, 4H),3.50-3.40 (br m, 5H), 2.84 (br s, 4H), 2.80 (m, 1H), 1.25 (d, 3H).

Example 1241-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E124) 2-Methyl-5-[(3R)-3-methyl-1-piperazinyl]quinoline

(2R)-2-Methylpiperazine (0.550 g; 2 eq), caesium carbonate (1.78 g; 2eq), palladium acetate (0.123 g; 0.2 eq) and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.513 g; 0.3 eq) were addedto a solution of 2-methyl-5-quinolinyl trifluoromethanesulfonate (D1)(0.8 g; 1 eq) in toluene (30 mL) under an inert atmosphere. The reactionmixture was stirred at reflux under nitrogen for 3 hours. The reactioncooled to room temperature, quenched using saturated aqueous ammoniumchloride solution (15 mL) and extracted with ethyl acetate (3×20 mL).The organic layers were combined, dried over sodium sulfate andconcentrated under reduced pressure. The crude was purified by flashchromatography on silica gel, eluting with dichloromethane-methanol(95:5) affording the title compound in 58% yield (0.383 g).

MS; (ES) m/z: 242.3 [MH]⁺. C₁₅H₁₉N₃ requires 241. ¹H-NMR (300 MHz,CDCl₃) δ(ppm): 8.40 (d, 1H), 7.76 (d, 1H), 7.61 (t, 1H), 7.29 (d, 1H),7.06 (d, 1H), 3.2 (m, 5H), 2.85 (t, 1H), 2.74 (s, 3H), 2.5 (t, 1 H) 1.25(d, 3H).

1-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E124)

A mixture of N,N-diisopropylethylamine (0.072 mL; 2 eq),2-methyl-5-[(3R)-3-methyl-1-piperazinyl]quinoline (0.05 g; 1 eq),2-[3-(2-oxo-1-imidazolidinyl)phenyl]ethyl methanesulfonate (0.07 g; 1.2eq) and acetonitrile (0.5 mL) was irradiated in a microwave reactor(PersonalChemistry Emrys™ Optimiser, 300 W, 180° C., 15 min). The darksolution was loaded on SCX ion-exchange cartridge (5 g) and eluted withmethanol followed by a solution of ammonia in methanol (1M). The basicfractions were concentrated under reduced pressure and further purifiedby flash chromatography on silica gel, eluting with a gradient fromdichloromethane to dichloromethane-methanol (98:2) affording the desiredfree base intermediate in 67% yield. The related dihydrochloride saltwas formed according to the description given in the general procedurefor the preparation of amides and their corresponding dihydrochloridesalts starting from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) to givethe title compound in 57% yield (0.03 g).

MS; (ES) m/z: 430.4 [MH]⁺. C₂₆H₃₁N₅O requires 429. ¹H-NMR (500 MHz,DMSO) δ(ppm): 10.8-10.66 (2bs, 1H); 8.54 (bs, 1H); 7.72 (bs, 1H); 7.61(s, 1H); 7.49 (m, 2H); 7.41 (t, 1H); 7.26 (m, 1H); 7.14 (m, 1H); 3.8 (t,3H); 3.2(t, 5H); 3.15/2.65 (bd-m, 7H); 2.5 (s, 3H); 1.3 (d, 3H).

Example 1253-(3-{2-[(2R)-2-Methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one(E125) 3-[3-(2-Hydroxyethyl)phenyl]-1 ,3-oxazolidin-2-one

The title compound was prepared in 48% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from 2-(3-bromophenyl)ethanol and 1,3-oxazolidin-2-one.

MS: (ES) m/z: 208 [MH⁺]. C₁₁H₁₃NO₃ requires 207. 1H-NMR (300 MHz, CDCl₃)δ(ppm): 7.45 (s, 1H), 7.32 (m, 2H), 7.03 (d, 1H), 4.48 (t, 2H), 4.05 (t,2H), 3.85 (bm, 2H), 2.87 (t, 2H), 1.58 (s, 1H).

2-[3-(2-Oxo-1,3-oxazolidin-3-yl)phenyl]ethyl methanesulfonate

The title compound was prepared in 93% yield according to the generalprocedure for the preparation of amides (Method B) starting fromstarting from 3-[3-(2-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one andmethanesulfonyl chloride. The crude material was purified on SPEcartridge (Silica) using as eluent a gradient from cyclohexane (100%) tocyclohexane-ethyl acetate (8:2) affording the final compound.

MS: (ES) m/z: 286 [MH⁺]. C₁₂H₁₅NO5S requires 285. 1H-NMR (300 MHz,CDCl3) δ(ppm): 7.5 (s, 1H), 7.3 (m, 2H), 6.95 (d, 1H), 4.3 (m, 4H), 4(t, 2H), 3 (t, 2H), 2.8 (s, 3H).

3-(3-{2-[(2R)-2-Methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one(E125)

The title compound was prepared in 33% yield using a similar procedureto E124 starting from 2-methyl-5-[(3R)-3-methyl-1-piperazinyl]quinolineand 2-[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl methanesulfonate.

MS; (ES) m/z: 431.4 [MH]⁺. C₂₆H₃₀N₄O₂ requires 430. 1H-NMR (500 MHz,d₆-DMSO) δ(ppm): 10.8-10.66 (2bs, 1H); 8.54 (bs, 1H); 7.72 (bs, 1H);7.61 (s, 1H); 7.49 (m, 2H); 7.41 (t, 1H); 7.26 (m, 1H); 7.14 (m, 1H);3.8 (t, 2H) 3.4 (m, 3H); 3.2-2.8 (bd-m, 9H), 2.71 (bm, 2H); 2.5 (s, 3H)1.41 (d, 3H).

Example 1261-(3-{2-[(2S)-2-Methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E126) 2-Methyl-5-[(3S)-3-methyl-1-piperazinyl]quinoline

The title compound was prepared in 27% yield using a similar procedureto Example 127 starting from (2S)-2-methylpiperazine and2-methyl-5-quinolinyl trifluoromethanesulfonate (D1).

MS; (ES) m/z: 242.3 [MH]⁺. C₁₅H₁₉N₃ requires 241. ^(1H-NMR ()300 MHz,CDCl₃) δ(ppm): 8.40 (d, 1H), 7.76 (d, 1H), 7.61 (t, 1H), 7.29 (d, 1H),7.06 (d, 1H), 3.2 (m, 5H), 2.85 (t, 1H), 2.74 (s, 3H), 2.5 (t, 1H) 1.1(d, 3H).

1-(3-{2-[(2S)-2-methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E126)

The title compound was prepared in 47% yield using a similar procedureto Example 127 starting from2-methyl-5-[(3S)-3-methyl-1-piperazinyl]quinoline and2-[3-(2-oxo-1-imidazolidinyl)phenyl]ethyl methanesulfonate.

MS; (ES) m/z: 430.4 [MH]⁺. C₂₆H₃₁N₅O requires 429. ¹H-NMR (500 MHz,DMSO) δ(ppm): 10.8-10.66 (2bs, 1H); 8.54 (bs, 1H); 7.72 (bs, 1H); 7.61(s, 1H); 7.49 (m, 2H); 7.41 (t, 1H); 7.26 (m, 1H); 7.14 (m, 1H); 3.8 (t,3H); 3.2(t, 5H); 3.15/2.65 (bd-m, 7H); 2.5 (s, 3H); 1.3 (d, 3H).

Example 1273-(3-{2-[(2S)-2-methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one(E127)

The title compound was prepared in 33% yield using a similar procedureto E124 starting from 2-methyl-5-[(3S)-3-methyl-1-piperazinyl]quinoline(D2) and 2-[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]ethyl methanesulfonate(Ex).

MS; (ES) m/z: 431.4 [MH]⁺. C₂₆H₃₀N₄O₂ requires 430. 1H-NMR (500 MHz,d₆-DMSO) δ(ppm): 10.8-10.66 (2bs, 1H); 8.54 (bs, 1H); 7.72 (bs, 1H);7.61 (s, 1H); 7.49 (m, 2H); 7.41 (t, 1H); 7.26 (m, 1H); 7.14 (m, 1H);4.48 (t, 2H); 4.1(t, 2H); 3.8/3.7-3 (bd-m, 11H), 2.71 (bm, 2H); 1.41(d,3H).

Example 1283-(3-{(1R,2S)-2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride and3-(3-{(1S,2R)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride (E128) 3-[3-(2-Hydroxyethyl)phenyl]-1,3-oxazolidin-2-one

A solution 2-(3-bromophenyl)ethanol (1.00 g, 5.00 mmol),2-oxazolidin-2-one (874 mg, 10.04 mmol), copper(I)iodide (96 mg, 0.50mmol), N,N′-dimethyl-1,2-ethanediamine (60 μL, 49 mg, 0.56 mmol) andpotassium carbonate (1.04 g, 7.50 mmol) were suspended in dioxane (6mL). The mixture was stirred under nitrogen for 2.5 h at 100° C. Afteraddition of copper(I)iodide (96 mg, 0.50 mmol) andN,N′-dimethyl-1,2-ethanediamine (60 μl, 49 mg, 0.56 mmol) stirring wascontinued for another 2 h at 100° C. After cooling down to roomtemperature, the mixture was poured into saturated aqueous ammoniumchloride solution and extracted with dichloromethane. The organic layerwas dried over magnesium sulfate and concentrated under reducedpressure. The crude compound was purified by flash chromatography onsilica gel, eluting with ethyl acetate-cyclohexane (1:1 to 1:0)affording the title compound in 64% yield (664 mg).

1H-NMR (300 MHz, CDCl₃) δ(ppm): 7.4 (s, 1H), 7.0-7.3 (m, 2H), 7.85 (m,1H), 4.25 (t, 2H), 3.85 (t, 2H), 3.65 (t, 2H), 2.65 (t, 2H), 1.50 (s,1H).

[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]acetaldehyde

1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martinperiodinane, 709 mg, 1.67 mmol) was added to a solution of3-[3-(2-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one (315 mg, 1.52 mmol) indichloromethane (10 mL). The mixture was stirred at room temperature for30 min, then washed with aqueous sodium hydroxide solution (1M, 10 mL).The separated organic layer the latter was dried over magnesium sulfateand concentrated under reduced pressure affording the title compound in89% yield (278 mg). The compound was used without further purificationin the next step.

1H-NMR (300 MHz, CDCl₃) δ(ppm): 9.73 (s, 1H), 7.49 (s, 1H), 7.3-7.4 (m,2H), 6.96 (m, 1H), 4.47 (t, 2H), 4.05 (t, 2H), 3.70 (s, 2H).

3-(3-{(1R,2S)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride and3-(3-{(1S,2R)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride (E128)

[3-(2-oxo-1,3-oxazolidin-3-yl)phenyl]acetaldehyde (275 mg, 1.34 mmol),para-toluenesulfonic acid hydrate (13 mg, 0.07 mmol) and2-methyl-5-(1-piperazinyl)quinoline (304 mg, 1.340 mmol) were dissolvedin toluene (30 mL) and heated for 2 h in a Dean-Stark-apparatus untilthe formation of the imine was complete (monitored by basicAl₂O₃-TLC-plates). After cooling to room temperature and evaporation ofthe solvent under reduced pressure, the crude imine was used withoutfurther purification.

Diiodomethane (0.22 mL, 718 mg, 2.68 mmol) was added to a solution ofdiethylzinc (1M in Hexanes, 2.0 mL, 2.00 mmol) in dry dichloromethane (5mL) at 0° C. under nitrogen and stirred for 10 min. The crude imine wasdissolved in dichloromethane (5 mL, dry) and added dropwise to thereaction mixture at 0° C. The reaction was warmed to room temperatureand stirring was continued for another 2 h. The mixture was quenchedwith methanol, then loaded onto an ion exchange cartridge (SCX-2) andeluted with methanol followed by ammonia in methanol (1M). The basicfractions were concentrated under vacuum and purified by flashchromatography on silica gel, eluting with cyclohexane-ethyl acetate(1:1 to 1:2) and finally isolated via mass-directed HPLC (Fraction LYNX)affording the title compound in 2% yield (10 mg). The free base could beconverted into its dihydrochloride salt by dissolving the compound indichloromethane and adding a 1M ethereal solution of HCl (2.1 eq)dropwise. A yellow solid precipitated and the suspension was stirred for15 min. The solvent was removed under reduced pressure affording a crudematerial which was triturated with ether. The title compound was thenrecovered by filtration (yield quantitative).

MS; (ES) m/z: 429 [MH⁺]. C₂₆H₂₈N₄O₂ requires 428. 1H-NMR (500 MHz,d₆-DMSO) δ(ppm): 11.39 (bs, 1H), 8.84 (bs, 1H), 7.89 (bs, 2H), 7.77 (bs,1H), 7.45 (d, 1H), 7.44 (s, 1H), 7.39 (bs, 1H), 7.34 (t, 1H), 6.96 (d,1H), 4.44 (t, 2H), 4.07 (t, 2H), 3.8-3.0 (bm, 9H), 2.86 (bs, 3H), 1.87(bs, 1H), 1.42 (bs, 1H).

Example 1292,4-Dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamidedihydrochloride and2,4-dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamidedihydrochloride (E129) 2-(3-Aminophenyl)ethanol

2-(3-Nitrophenyl)ethanol (836 mg, 5.00 mmol) and Pd (10% on charcoal,200 mg) were suspended in dry methanol (10 mL). After the addition ofammonium formate (1.450 g, 23 mmol) a slightly exothermic andeffervescent reaction was observed. After stirring for 1 h at roomtemperature the mixture was filtered over celite. The filtrate wasevaporated and the residue dissolved in ethyl acetate. After washingwith saturated aqueous sodium hydrogencarboante solution, water andbrine the organic layer was dried (magnesium sulfate) and the solventremoved under reduced pressure affording the title compound in 54% yield(373 mg) as a white solid.

MS; (ES) m/z: 138 [MH⁺]. C₈H₁₁NO requires 137. 1H-NMR (300 MHz, d₆-DMSO)δ(ppm): 6.80 (t, 1H), 6.25-6.35 (m, 3H), 4.85 (s, 2H), 4.50 (t, 1H),3.45 (dt, 2H), 2.45 (t, 2H).

N-[3-(2-hydroxyethyl)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide

2-(3-Aminophenyl)ethanol (1.202 g, 8.76 mmol) was added to a solution of2,4-dimethyl-1,3-thiazole-5-carboxylic acid (1.652 g, 10.51 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.015 g,10.51 mmol) and 1-hydroxybenzotriazole (1.420 g, 10.51 mmol) in dry DMF(20 mL). The mixture was stirred for 14 h then the DMF was removed underreduced pressure and the residue was partitioned between DCM andsaturated aqueous sodium hydrogencarbonate solution. The organic layerwas dried over magnesium sulfate and concentrated under reducedpressure. The crude compound was purified by flash chromatography onsilica gel, eluting with ethyl acetate-cyclohexane (1:1 to 1:0)affording the title compound in 73% yield (1.772 g).

MS; (ES) m/z: 277 [MH⁺]. C₁₄H₁₆N₂O₂S requires 276. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 9.95 (s, 1H), 7.40-7.50 (m, 2H), 7.19 (t, 1H), 6.92 (d,1H), 4.60 (t, 1H), 5.57 (dd, 2H), 2.66 (t, 2H), 2.61 (s, 3H), 2.49 (s,3H).

2,4-Dimethyl-N-[3-(2-oxoethyl)phenyl]-1,3-thiazole-5-carboxamide

The title compound was synthesised according to the procedure describedfor E128 usingN-[3-(2-hydroxyethyl)phenyl]-2,4-dimethyl-1,3-thiazole-5-carboxamide(800 mg, 2.895 mmol) and purified by flash chromatography on silica geleluting with DCM-methanol (95:5) affording 519 mg (65%).

MS; (ES) m/z: 275 [MH+]. C₁₄H₁₄N₂O₂S requires 274. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 9.85 (s, 1H), 7.60 (m, 1H), 7.3-7.5 (m, 3H), 7.00 (d,1H), 3.70 (s, 2H), 3.65 (s, 6H).

2,4-Dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamidedihydrochloride and2,4-dimethyl-N-(4-{(1R,2S)-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]cyclopropyl}phenyl)-1,3-thiazole-5-carboxamidedihydrochloride (Example 129)

The title compound was synthesised according to the procedure describedfor E128 using2,4-dimethyl-N-[3-(2-oxoethyl)phenyl]-1,3-thiazole-5-carboxamide (D6, 85mg, 0.30 mmol) affording the enantiomeric mixture (5 mg, 3%).

MS; (ES) m/z: 498 [MH⁺]. C₂₉H₃₁N₅OS requires 497. 1H-NMR (500 MHz,d₆-DMSO) δ(ppm): 11.11 (bs, 1H), 10.09 (s, 1H), 8.78 (bs, 1H), 7.85 (bs,2H), 7.73 (bs, 1H), 7.6 (s, 1H), 7.47 (d, 1H), 7.38 (bs, 1H), 7.29 (t,1H), 6.97 (d, 1H), 3.8-3.0 (bm, 9H), 2.7-2.9 (bs, 4H), 2.65 (s, 3H),2.53 (s, 3H), 1.85 (bs, 1H), 1.4 (bs, 1H).

Example 1301-Methyl-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(E130)

To a stirred solution of1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(E85) in THF was added methyl iodide (1 eq.), followed by sodium hydride(1.2 eq), and the reaction was stirred for 60 minutes. The mixture wasloaded onto an ion-exchange cartridge (SCX-2) and eluted with methanolfollowed by ammonia in methanol (1M). The basic fractions wereconcentrated under vacuum and purified by column chromatography (SPEcartridge, Silica) using as eluent a gradient from DCM-methanol (99:1)to DCM-methanol (98:2) affording the final compound (45% yield).

MS: (ES/+) m/z: 430 [MH⁺] C₂₆H₃₁N₅O₂ requires 429. 1H-NMR (400MHz,d₆-DMSO) δ(ppm): 11.19 (1H, bs), 8.94 (1H, bs), 7.99 (2H, bs), 7.84 (1H,bd), 7.6 (1H, bs), 7.48 (1H, bs), 7.45 (1H, d), 7.32 (1H, t), 6.96 (1H,d), 3.81 (2H, t), 3.73 (2H, bd), 3.7-3.2 (10H, m), 3.13 (2H, m), 2.93(3H, bs), 2.79 (3H, s).

Example 131N-(2-(Methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamidedihydrochloride (E131) 2-(Methoxy)-3-nitrobenzaldehyde

To a solution of 2-hydroxy-3-nitrobenzaldehyde in DMF was addedportionwise cesium carbonate (3 eq), followed by iodomethane (1.2 eq.).The solution was warmed to 60° C. for 2 hours, then cooled to roomtemperature and filtered. The filtrate was concentrated under vacuum andpurified by column chromatography on SPE cartridge (Silica) using aseluent cyclohexane-ethyl acetate (8:2) to give the product in 72% yield.

1H-NMR (300 MHz, CDCl₃) δ(ppm): 10.28 (1H, s), 7.95 (2H, m), 7.23 (1H,m), 3.97 (3H, s).

[2-(Methoxy)-3-nitrophenyl]acetaldehyde

To a stirred solution of 2-(methoxy)-3-nitrobenzaldehyde in THF wereadded 18-Crown-6 (0.2 eq), (methoxymethyl)triphenylphosphonium chloride(2 eq) and potassium carbonate (6.5 eq). The resulting suspension waswarmed to 60° C. for 2 hours then cooled to room temperature andfiltered. The filtrate was concentrated under vacuum and purified bychromatography on a silica cartridge (eluent cyclohexane-ethyl acetate,9:1) to give a mixture of2-(methoxy)-1-[(E)-2-(methoxy)ethenyl]-3-nitrobenzene and2-(methyloxy)-1-[(Z)-2-(methyloxy)ethenyl]-3-nitrobenzene. The alkenemixture was dissolved in THF and 6N hydrochloric acid (1:1), and stirredfor 1 hour. The solution was made basic with aqueous sodium carbonatesolution and extracted with DCM. The organic layer was washed (water,brine), dried (sodium sulfate) and concentrated under vacuum to give thetitle compound (54% overall yield).

1H-NMR (300 MHz, CDCl₃) δ(ppm): 9.75 (1H, s), 7.8 (1H, d), 7.4 (1H, d),7.2 (1H, m), 3.85 (3H, s), 3.8 (2H, s).

2-(Methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline

To a stirred solution of [2-(methoxy)-3-nitrophenyl] in acetonitrile wasadded 2-methyl-5-(1-piperazinyl)quinoline and the solution was stirredat room temperature for 15 minutes. Sodium triacetoxyborohydride wasadded and the suspension was stirred for 75 minutes. The intermediate,2-methyl-5-(4-{2-[2-(methoxy)-3-nitrophenyl]ethyl}-1-piperazinyl)quinoline,was recovered by ion-exchange chromatography [SCX-2 cartridge;methanol-ammonia/methanol (1M), (1:0)→(0:1)]. The title compound wasobtained in 71% overall yield from2-methyl-5-(4-{2-[2-(methoxy)-3-nitrophenyl]ethyl}-1-piperazinyl)quinolineaccording to the procedure contained within Description 6 (D6).

MS: (ES/+) m/z: 377 [MH⁺] C₂₃H₂₈N₄O requires 376. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.37 (1H, d), 7.68 (1H, d), 7.57 (1H, t), 7.22 (1H, d),7.07 (1H, d), 6.88 (1H, t), 6.63 (2H, d), 3.76 (4H, bs), 3.13 (4H, bs),2.95-2.6 (10H, vbm).

N-(2-(Methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamidedihydrochloride (E131)

The title compound was prepared in 42% yield according to the generalprocedure for the preparation of amides (Method B) starting fromstarting from2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}anilineand acetyl chloride.

MS: (ES/+) m/z: 419 [MH⁺] C₂₅H₃₀N₄O₂ requires 418. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.64 (1H, b), 9.38 (1H, s), 8.77 (1H, bs), 7.84 (3H,m), 7.72 (1H, bs), 7.39 (1H, s), 7.09 (2H, m), 3.77 (3H, s), 3.52 (2H,m), 3.6-3.3 (8H, m), 3.15 (2H, m), 2.83 (3H, s), 2.14 (3H, s).

Example 132N-(2-(Methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)methanesulfonamidedihydrochloride (E132)

The title compound was prepared in 72% yield according to the generalprocedure for the preparation of amides (Method B) starting from2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}anilineand methanesulfonyl chloride.

MS: (ES/+) m/z: 455 [MH⁺] C₂₅H₃₀N₄O₂ requires 454. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.68 (1H, b), 9.19 (1H, s), 8.8 (1H, bs), 7.87 (2H,bs), 7.72 (1H, bs), 7.39 (1H, s), 7.33 (1H, m), 7.16 (2H, m), 3.82 (3H,s), 3.77 (2H, m), 3.6-3.3 (8H, m), 3.15 (2H, m), 3.11 (3H, s), 2.83 (3H,s).

Example 1333-(2-(Methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride (E133)

The title compound was prepared in 63% yield according to the generalprocedure for the synthesis of cyclic ureas and carbamates (Method G)starting from2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}anilineand (2-bromoethyl)carbamyl chloride.

MS: (ES/+) m/z: 447 [MH⁺] C₂₆H₃₀N₄O₃ requires 446. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.73 (1H, b), 8.82 (1H, bs), 7.88 (2H, bs), 7.75 (1H,bs), 7.42 (1H, s), 7.38 (1H, dd), 7.31 (1H, dd), 7.21 (1H, t), 4.51 (2H,t), 3.97 (2H, t), 3.81 (3H, s), 3.77 (2H, m), 3.6-3.3 (8H, m), 3.17 (2H,m), 2.85 (3H, s).

Example 1341-(2-(Methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E134)

The title compound was prepared in 38% yield according to the generalprocedure for the synthesis of cyclic ureas and carbamates (Method G)starting from2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}anilineand 1-chloro-2-isocyanatoethane.

MS: (ES/+) m/z: 446 [MH⁺] C₂₆H₃₁N₅O₂ requires 445. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.78 (1H, b), 8.85 (1H, bs), 7.9 (2H, bs), 7.76 (1H,bs), 7.42 (1H, s), 7.3 (1H, dd), 7.21 (1H, dd), 7.13 (1H, t), 6.79 (1H,bs), 3.79 (3H, s), 3.78 (2H, t), 3.6-3.3 (12H, m), 3.15 (2H, m), 2.87(3H, s).

Example 1351-Methyl-3-(2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E135)

The title compound was prepared in 20% yield according to proceduredescribed for Example 130 starting from1-(2-(methoxy)-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinoneand iodomethane.

MS: (ES/+) m/z: 460 [MH⁺] C₂₆H₃₁N₅O₂ requires 459. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.95 (1H, b), 10.7-10.5 (1H, b), 8.88 (1H, bs), 7.93(2H, bs), 7.8 (1H, bs), 7.44 (1H, s), 7.27 (1H, dd), 7.21 (1H, dd), 7.14(1H, t), 3.77 (2H, m), 3.76 (3H, s), 3.7 (2H, t), 3.6-3.3 (8H, m), 3.17(2H, m), 2.9 (5H, m), 2.87 (3H, s).

Example 136N-(4-Fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide(E136)

The title compound was prepared in 66% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinolineand acetamide.

MS: (ES/+) m/z: 407 [MH⁺]. C₂₄H₂₇FN₄O requires 406. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.69 (br s, 1H), 10.08 (s, 1H), 8.82 (br s, 1H), 7.88(br s, 2H), 7.75 (br s, 1H), 7.74 (dd, 1H), 7.41 (m, 1H), 7.19 (t, 1H),3.77 (dd, 2H), 3.61-3.30 (m, 8H), 3.14 (m, 2H), 2.85 (s, 3H), 2.06 (s,6H).

5-{4-[2-(5-Bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinoline

The title compound was prepared in 95% yield from(5-bromo-2-fluorophenyl)acetaldehyde (0.98 g),2-methyl-5-(1-piperazinyl)quinoline (0.51 g) and sodiumtriacetoxyborohydride (0.95 g) according to the procedure described forExample 131.

MS: (ES/+) m/z: 428, 430 [MH⁺]. C₂₂H₂₃BrFN₃ requires 427, 429. 1H-NMR(300 MHz, CDCl₃) δ(ppm): 8.37 (d, 1H), 7.69 (d, 1H), 7.52 (t, 1H), 7.40(dd, 1H), 7.26-7.18 (m, 2H), 7.07 (dd, 1H), 6.88 (t, 1H), 3.11 (m, 4H),2.90-2.75 (m, 6H), 2.69 (s, 3H) and 2.68 (m, 2H).

(5-Bromo-2-fluorophenyl)acetaldehyde

The title compound was prepared from(E/Z)-2-(5-bromo-2-fluorophenyl)ethenyl methyl ether according to theprocedure described for Example 131 and used without furtherpurification or characterisation.

(E/Z)-2-(5-Bromo-2-fluorophenyl)ethenyl methyl ether

The title compound was prepared in 48% yield from5-bromo-2-fluorobenzaldehyde (2.00 g) and(methoxymethyl)triphenylphosphonium chloride (4.05 g) according to theprocedure described for Example 131.

1H-NMR (300 MHz, CDCl₃) δ(ppm): 8.07 (d, 0.5H), 7.30-7.00 (m, 2H), 6.72(m, 1H), 6.17 (d, 0.5H), 5.65 (d, 0.5H), 5.32 (d, 0.5H), 3.68 (s, 1.5H)and 3.59 (s, 1.5H).

Example 137N-(4-Fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,2-dimethylpropanamide(E137)

The title compound was prepared in 52% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinolineand 2,2-dimethylpropanamide.

MS: (ES/+) m/z: 449 [MH⁺]. C₂₇H₃₃FN₄O requires 448. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.56 (br s, 1H), 9.33 (s, 1H), 8.77 (br s, 1 H), 7.84(br s, 2H), 7.8 (dd, 1H), 7.71 (br s, 1H), 7.51 (m, 1H), 7.39 (br s,1H), 7.19 (t, 1H), 3.77 (dd, 2H), 3.61-3.30 (m, 8H), 3.14 (m, 2H), 2.83(s, 3H), 1.24 (s, 9H).

Example 138N-(4-Fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)methanesulfonamide(E138)

The title compound was prepared in 69% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinolineand methanesulfonamide.

MS: (ES/+) m/z: 434 [MH⁺]. C₂₅H₂₈FN₅O requires 433. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.92 (br s, 1H), 9.78 (s, 1H), 8.77 (br s, 1 H), 7.92(br s, 2H), 7.78 (br s, 1H), 7.43 (br s, 1H), 7.3-7.15 (m, 3H), 3.76(dd, 2H), 3.6-3.3 (m, 8H), 3.17 (m, 2H), 3.01 (s, 3H), 2.85 (s, 3H).

Example 1391-(4-Fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(E139)

The title compound was prepared in 35% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinolineand 2-imidazolidone.

MS: (ES/+) m/z: 434 [MH⁺]. C₂₃H₂₇FN₄OS requires 433. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.64 (br s, 1H), 8.33 (br s, 1H), 7.88 (br s, 2H),7.74 (br s, 1H), 7.67 (dd, 1H), 7.45 (dd, 1H), 7.4 (br s, 1H), 7.21 (t,1H), 7.02 (s, 1H), 3.86 (t, 2H), 3.77 (dd, 2H), 3.6-3.3 (m, 1OH), 3.16(m, 2H), 2.85 (s, 3H).

Example 1403-(4-Fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one(E140)

The title compound was prepared in 95% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(5-bromo-2-fluorophenyl)ethyl]-1-piperazinyl}-2-methylquinolineand 2-imidazolidone.

MS: (ES/+) m/z: 435 [MH⁺]. C₂₅H₂₈FN₅O requires 434. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.73 (br s, 1H), 8.85 (br s, 1H), 7.89 (br s, 2H),7.77 (br s, 1H), 7.68 (dd, 1H), 7.5 (dd, 1H), 7.43 (br s, 1H), 7.39 (t,1H), 4.47 (dd, 2H), 4.09 (dd, 2H), 3.77 (dd, 2H), 3.6-3.3 (m, 8H), 3.19(m, 2H), 2.87 (s, 3H).

Example 1411-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-imidazolidinedionedihydrochloride (E141)

5-{4-[2-(3-Iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (46 mg,0.100 mmol), hydantoin (44.8 mg, 0.444 mmol), potassium carbonate (23.1mg, 0.167 mmol), copper(I)iodide (107 mg, 0.561 mmol) andN,N′-dimethyl-1,2-ethanediamine (60 □L, 50 mg, 0.563 mmol) weredissolved in dioxane (2 mL) and heated at 150□C. for 75 min viamicrowave irradiation. The mixture was cooled to room temperature andpartitioned between water and ethyl acetate. The organic layer was driedover magnesium sulfate and concentrated under reduced pressure. Thecrude compound was purified by flash chromatography on silica gel,eluting with dichloromethane-methanol (97:3 to 95:5) afforded the titlecompound in 23% yield (10 mg) as the first-eluting hydantoinregioisomer.

MS: (ES/+) m/z: 430 [MH⁺] C₂₅H₂₇N₅O₂ requires 429. 1H-NMR (400 MHz,d₆-DMSO) δ (ppm): 11.12 (1H, bs), 8.3 (1H, d), 7.55 (2H, m), 7.48 (1H,bs), 7.4 (1H, bd), 7.35 (1H, d), 7.24 (1H, t), 7.06 (1H, dd), 6.97 (1H,bd), 4.4 (2H, s), 3(4H, bs), 2.8-2.5 (8H, bm), 2.59 (3H, s).

Example 1423-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-imidazolidinedionedihydrochloride (E142)

The title compound was prepared according to the method described forExample 144 and isolated in 18% yield (8 mg) as the second-elutinghydantoin regioisomer.

MS: (ES/+) m/z: 430 [MH⁺] C₂₅H₂₇N₅O₂ requires 429. 1H-NMR (400 MHz,d₆-DMSO) (ppm): 8.23 (1H, bd), 8.24 (1H, bs), 7.55 (2H, bs), 7.34 (1H,bd), 7.4-7.0 (5H, m), 4.02 (2H, s), 3(4H, bs), 2.81-2.59 (8H, bm), 2.59(3H, s).

Example 143 (R or S)3-(3-{2-[(2R)-2-Methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride (E143)

A mixture of 3-[3-(2-oxopropyl)phenyl]-1,3-oxazolidin-2-one and2-methyl-5-[(3R)-3-methyl-1-piperazinyl]quinoline (1.2 eq) was suspendedin titanium(IV)isopropoxide (2 eq), and stirred for 12 hours. Thesolution was gently warmed to 60° C. and stirred for 1 hour, thenmethanol was added, followed by sodium borohydride (9 eq) and themixture was stirred for a further 4 hours. The solution was poured intoaqueous ammonium chloride solution and extracted with DCM. The organicphase was concentrated under vacuum and purified by chromatography (SPEcartridge, silica) using as eluent a gradient fromdichloromethane-methanol (99:1) to (98:2) affording the diastereomericmixture (34% yield). Separation using preparative HPLC (Chiralpak AD 10□m, 250×20 mm; mobile phase: A: n-Hexane, B: isopropanol+0.1%2-propanol; gradient: isocratic 20% B; flow rate: 7 mL/min; UVwavelength range: 220 nm; analysis time: 60 min) produced the titlecompound free base as the first-eluting diastereoisomer. The free basewas dissolved in dichloromethane and treated with 1M ethereal hydrogenchloride solution (2.1 eq). A yellow solid precipitated and thesuspensions were stirred for 15 min. The solvent was removed underreduced pressure affording a solid, which was triturated with ether. Thetitle compound was then recovered by filtration (yield quantitative).

MS: (ES/+) m/z: 445 [MH⁺] C₂₇H₃₂N₄O₂ requires 444. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.96 (1H, vbs), 8.96 (1H, vbs), 7.9 (2H, bs), 7.76(1H, bs), 7.62 (1H, s), 7.4 (3H, m), 7.15 (1H, d), 4.47 (2H, t), 4.1(2H, m), 4-3.2 (10H, vbm), 2.87 (3H, bs), 1.42 (3H, d), 1.24 (3H, d).

Example 144 (S or R)3-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-onedihydrochloride (E144)

The title compound was isolated as the second-eluting diastereoisomerfrom the procedure described for Example 143.

MS: (ES/+) m/z: 445 [MH⁺] C₂₇H₃₂N₄O₂ requires 444. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 10.82 (1H, vbs), 8.97 (1H, vbs), 7.92 (2H, bs), 7.78(1H, bs), 7.64 (1H, s), 7.4 (3H, m), 7.14 (1H, d), 4.47 (2H, t), 4.11(2H, m), 4-2.7 (10H, vbm), 2.89 (3H, bs), 1.5 (3H, d), 1.32 (3H, d).

Example 1451-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-onedihydrochloride (E145)

A mixture of5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (117 mg,0.256 mmol), 1,3-dihydro-2H-imidazol-2-one (84 mg, 1.023 mmol, Whitney,R. A., Tet. Lett. 1981, 22, 2063-2066), potassium carbonate (53 mg,0.384 mmol), copper(I)iodide (244 mg, 1.28 mmol) andN,N′-dimethyl-1,2-ethanediamine (163 □L, 135 mg, 1.536 mmol) and dioxane(2.5 mL) was heated at 150° C. for 90 min under microwave irradiation.The mixture was cooled to room temperature and partitioned between waterand ethyl acetate. The organic layer was dried over magnesium sulfateand concentrated under reduced pressure. The crude compound was purifiedby flash chromatography on silica gel, eluting withdichloromethane-methanol (97:3) affording the title compound in 20%yield (23 mg). The free base was converted into its dihydrochloride saltby dissolving the compound in dichloromethane and adding a 1M etherealsolution of HCl (2.1 eq) dropwise. A yellow solid precipitated and thesuspension was stirred for 15 min. The solvent was removed under reducedpressure; the residue was triturated with ether. The title compound wasthen recovered by filtration (yield quantitative).

MS: (ES/+) m/z: 414 [MH⁺] C₂₅H₂₇N₅O requires 413. 1H-NMR (400 MHz,d₆-DMSO) δ (ppm): 10.75 (1H, bs), 10.28 (s, 1H), 8.78 (bs, 1H), 7.84(bs, 2H), 7.7 (bs, 1H), 7.69 (t, 1H), 7.56 (dd, 1H), 7.38 (t, 1H), 7.36(bs, 1H), 7.13 (d, 1H), 6.92 (dd, 1H), 6.58 (dd, 1H), 3.69 (bd, 2H),3.5-3.2 (8H), 3.12 (m, 2H), 2.81 (bs, 3H).

Example 1461-Methyl-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-onedihydrochloride (E146)

To a solution of1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-one(E145 free-base, 23 mg, 0.056 mmol) in dry DMF (1 mL) at 0° C. was addedsodium hydride (3.5 mg, 0.084 mmol, 60% suspension in mineral oil).After stirring for 30 min methyl iodide was added (4 μL, 9.5 mg, 0.067mmol) and stirring was continued for 6 h. Methanol was added, themixture was loaded onto an ion-exchange cartridge (SCX-2) and the crudeproduct liberated by elution with ammonia in methanol solution (1N). Thecrude compound was purified by flash chromatography on silica gel,eluting with dichloromethane-methanol (99:1 to 97:3) affording the titlecompound in 23% yield (5.5 mg). The free base was converted into itsdihydrochloride salt by dissolving the compound in dichloromethane andadding a 1M ethereal solution of HCl (2.1 eq) dropwise. A yellow solidprecipitated and the suspension was stirred for 15 min. The solvent wasremoved under reduced pressure; the residue was triturated with ether.The title compound was then recovered by filtration (yieldquantitative).

MS: (ES/+) m/z: 428 [MH⁺] C₂₆H₂₉N₅O requires 427. 1H-NMR (400 MHz,d₆-DMSO) (ppm): 11.5 (2vbs, 1H), 8.79 (vbs, 1H), 7.87 (bs, 2H), 7.74(bs, 2H), 7.63 (d, 1H), 7.46 (t, 1H), 7.4 (bs, 1H), 7.21 (d, 1H), 7.04(d, 1H), 6.78 (d, 1H), 3.8-2.9 (vbm, 12H), 3.21 (s, 3H), 2.85 (bs, 3H).

Example 147N-(3-{2-[4-(2-methyl-5-quinazolinyl)-1-piperazinyl]ethyl}phenyl)methanesulfonamide(E147)

A mixture of 2-methyl-5-(1-piperazinyl)quinazoline (50 mg),2-{3-[(methylsulfonyl)amino]phenyl}ethyl methanesulfonate (65 mg),diisopropylethylamine (192 μL) and DMF (0.5 mL) was heated to 100° C. ina sealed tube and stirred for 24 hours. The mixture was cooled to roomtemperature and partitioned between aqueous ammonium chloride solutionand ethyl acetate. The organic layer was washed (water, brine), dried(sodium sulfate) and concentrated in vacuo. The residue was purified bycolumn chromatography [SiO₂; DCM-MeOH: (100:0)→(95:5)] to give the titlecompound as a beige foam (35 mg).

MS; (ES) m/z: 426 [MH⁺]. C₂₂H₂₇N₅O₂S requires 425. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 9.65 (s, 1H), 9.48 (s, 1H), 7.82 (t, 1H), 7.50 (d, 1H),7.24 (t, 1H), 7.15 (d, 1H), 7.11 (s, 1H), 7.04 (d, 1H), 7.01 (d, 1H),3.12 (m, 4H), 2.97 (s, 3H), 2.75 (m, 6H), 2.73 (s, 3H) and 2.63 (m, 2H).

2-{3-[(Methylsulfonyl)amino]phenyl}ethyl methanesulfonate

The title compound was prepared from 3-aminophenethyl alcohol (U.S. Pat.No. 2,641,602) and methanesulfonyl chloride (2 eq.) according to theprocedure contained within description 4. The product was usedimmediately without further purification or characterisation.

2-Methyl-5-(1-piperazinyl)quinazoline

To a stirred solution of 2-methyl-5-fluoro-quinazoline (WO2003068772,Chem. Abstr. 139:197493, 2 g; 12.3 mmol) in dry dimethylformamide (10mL) were added triethylamine (3.4 mL; 2 eq) and piperazine (11 g; 10eq). The reaction mixture was stirred under nitrogen at 120° C. for 4 h,then cooled to room temperature, poured into water (10 mL) and extractedwith ethyl acetate (5×15 mL). The organic layers were combined, driedover sodium sulfate and concentrated in vacuo. The crude product waspurified by ion-exchange chromatography [SCX-2; MeOH-1M NH₃/MeOH(1:0)→(0:1)] to afford the title compound as a yellow solid (1.8 g;yield 64%).

MS; (ES) m/z: 229.2 [MH⁺]. C₁₁H₈F₃NO₃S requires 228. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 9.58 (s, 1H), 7.89 (t, 1H), 7.62 (d, 1H), 7.27 (d, 1H),3.25 (m, 8H); 2.91 (s, 3H).

Example 148N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N-(methylsulfonyl)methanesulfonamide(E148)

To a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (370 mg) andtriethylamine (178 μL) in DCM (3 mL) was added methanesulfonyl chloride(33 □L). The mixture was stirred for 18 h, then partitioned betweensaturated aqueous sodium hydrogencarbonate solution and DCM. The organiclayer was washed with water, dried and concentrated in vacuo. Theresidue was purified by column chromatography [SiO₂; DCM-MeOH,(20:0)→(20:1)] to give the title compound (342 mg).

MS; (ES) m/z: 503 [MH⁺]. C₂₄H₃₀N₄O₄S₂ requires 502. 1H-NMR (400 MHz,d₆-DMSO) δ(ppm): 8.33 (d, 1H), 7.6-7.5 (m, 2H), 7.42-7.30 (m, 5H), 7.09(dd, 1H), 3.52 (s, 6H), 3.02 (bm, 4H), 2.86 (t, 2H), 2.8-2.6 (m, 6H) and2.62 (s, 3H).

Example 149N-methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide (E149)

A solution ofN-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)acetamide(50 mg) was dissolved in THF (2.5 mL) and sodium hydride (60% w/w oildispersion, 0.005 g, 1 eq.) was added at 0° C. After 5 minutesiodomethane was added (5 uL, 1.0 eq.) and the mixture was warmed to roomtemperature. After 10 h the solution was partitioned between water (3mL) and ethyl acetate (3×5 mL). The combined organic extracts werewashed with brine, dried over sodium sulfate and concentrated undervacuum. The crude was purified by flash chromatography on silica gel,eluting with a gradient from dichloromethane to dichloromethane-methanol(98:2) affording the title compound in 61% yield (0.02 g).

MS: (ES) m/z: 403.4 [MH⁺]. C₂₅H₃₁ClNO₄ requires 402. 1H-NMR (300 MHz,D6-DMSO) δ(ppm): 10.85 (bs, 1H), 8.79 (bs, 1H), 8-7 (bm, 16H), 3.8-3.0(bm, 15H), 2.84 (bs, 3H), 1.79 (bs, 3H).

Example 150N-(1-Methylethyl)-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)urea(E150)

The title compound was prepared from3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 30 mg),isopropyl isocyanate (10.2 μL) using toluene (1 mL) as solvent accordingto Method E. Yield 23 mg.

MS: (ES) m/z: 432 [MH⁺]. C₂₆H₃₃N₅O requires 431. 1H-NMR (400 MHz, CDCl₃)δ(ppm): 8.40 (d, 1H), 7.73 (d, 1H), 7.60 (t, 1H), 7.3-7.2 (m, 3H), 7.09(d, 2H), 6.99 (d, 1H), 6.15 (s, 1H), 4.49 (d, 1H), 4.02 (m, 1H),3.16-2.83 (m, 12H) and 1.2, (d, 6H).

Example 151N-methyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)methanesulfonamide(E151)

A sample ofN-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)methanesulfonamide,hydrochloride salt (E43, 25 mg) was partitioned between saturatedaqueous sodium hydrogencarbonate solution and DCM. The organic phase wasdried over sodium sulfate and concentrated in vacuo to give thefree-base (18.5 mg), which was dissolved in THF (1.5 mL) and cooled to0° C. To the stirred solution was added sodium hydride (60%, 5 mg). Themixture was stirred for 30 minutes then iodomethane (5 μL) was added.The mixture was warmed to room temperature and stirred for 18 h. Themixture was cooled to 0° C. and further portions of sodium hydride (60%,5 mg) and iodomethane (5 μL) were added. The mixture was warmed to roomtemperature and stirred for 24 h, then partitioned between aqueousammonium chloride solution and DCM. The organic layer was washed(water), dried (sodium sulfate) and concentrated in vacuo. The residuewas purified using column chromatography (SiO₂; DCM-MeOH, 97:3) to givethe title compound (5 mg).

MS; (ES) m/z: 439 [MH⁺]. C₂₄H₃₀N₄O₂S requires 438. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.32 (d, 1H), 7.70 (d, 1H), 7.58 (t, 1H), 7.30-7.20 (m,3H), 7.17 (s, 1H), 7.10-7.00 (m, 3H), 3.78 (t, 2H), 3.37 (t, 2 H), 3.12(m, 4 H), 2.87 (m, 2H), 2.80 (m, 4H), 2.72 (m, 2H), 2.71 (s, 3H) and2.52 (quint., 2H).

Example 1521-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-pyrrolidinone(E152) 1-[3-(2-Hydroxyethyl)phenyl]-2-pyrrolidinone

The title compound was prepared in 15% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from 2-(3-bromophenyl)ethanol and 2-pyrrolidinone.Purification was achieved by flash chromatography on silica gel elutingwith ethyl acetate.

1H-NMR (300 MHz, CDCl₃) δ(ppm): 7.60 (s, 1H), 7.40 (d, 1H), 7.30 (t,1H), 7.00 (d, 1H), 4.40 (t, 2H), 3,85 (m, 4H), 2.85 (t, 2H), 2.60 (t,2H), 2.10 (q, 2H).

2-[3-(2-oxo-1-pyrrolidinyl)phenyl]ethyl methanesulfonate

Methanesulfonyl chloride (0.124 mL) was added dropwise to a stirredsolution of 1-[3-(2-hydroxyethyl)phenyl]-2-pyrrolidinone (0.30 g) andtriethylamine (0.42 mL) in dichloromethane (10 mL) at room temperatureunder an inert atmosphere. The solution was stirred for 2 hours. Thereaction mixture was diluted with ethyl acetate (50 mL) and washed withwater (50 mL), aqueous hydrochloric acid (1N, 2×50 mL), a saturatedaqueous solution of sodium hydrogencarbonate (50 mL) and brine (50 mL).The organic layer was dried over sodium sulfate and concentrated underreduced pressure. The crude was purified by flash chromatography onsilica gel, eluting with ethyl acetate-cyclohexane (50:50) to afford thetitle compound in 93% yield (0.384 g).

1H-NMR (300 MHz, CDCl₃) δ(ppm): 7.60 (s, 1H), 7.40 (d, 1H), 7.30 (t,1H), 7.00 (d, 1H), 4.40 (t, 2H), 3,85 (t, 2H), 3.05 (t, 2H), 2.85 (s,3H), 2.60 (t, 2H), 2.15 (q, 2H).

1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-pyrrolidinone(E152)

N,N-Diisopropylethylamine (0.23 mL) was added to a solution of2-methyl-5-(1-piperazinyl)quinoline (D3) (0.05 g) and2-[3-(2-oxo-1-pyrrolidinyl)phenyl]ethyl methanesulfonate (0.071 g) indimethylformamide (1 mL) and the resulting mixture was heated to 100° C.for 18 hours, then cooled to room temperature. The reaction mixture wasdiluted with ethyl acetate (50 mL) and washed with water (50 mL), amixture of water and brine (1:1, 2×50 mL) and brine (50 mL). The organiclayer was dried over sodium sulfate and concentrated under reducedpressure. The crude was purified by flash chromatography on silica gel,eluting with methanol-ethyl acetate (90:10) affording the title compoundin 77% yield (0.07 g).

MS; (ES) m/z: 415.3 [MH]⁺, 208.4 [M+2H]²⁺. C₂₆H₃₀N₄O requires 414.1H-NMR (300 MHz, CDCl₃) δ(ppm): 8.37 (d, 1H), 7.70 (d, 1H), 7.57 (m,2H), 7.37 (m, 1H), 7.25 (m, 2H), 7.07 (d, 1H), 7.03 (bd, 1H), 3.85 (t,2H), 3.13 (bm, 2H), 2.9-2.75 (bm, 8H), 2.70 (s, 3H), 2.60 (t, 2H), 2.15(q, 2H).

Example 1535-(4-{2-[3-(1,1-Dioxido-2-isothiazolidinyl)phenyl]ethyl}-1-piperazinyl)-2-methylquinoline(E153)

To a stirred solution of3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 30 mg)in pyridine (0.5 mL) was added 2-chloroethylsulfonyl chloride (13 μL).The mixture was stirred 1 h then concentrated in vacuo and partitionedbetween saturated aqueous sodium hydrogencarbonate solution and DCM. Theorganic layer was washed (water), dried (sodium sulfate) andconcentrated in vacuo. The residue was dissolved in THF (1 mL) andcooled to 0° C. with stirring. To the stirred solution was added sodiumhydride (60%, 20 mg). The mixture was warmed to room temperature andleft to stand for 4 days. The reaction was diluted with water andconcentrated in vacuo. The residue was partitioned between DCM andwater. The organic layer was washed (water), dried (sodium sulfate) andconcentrated in vacuo. The residue was purified by column chromatography(SiO₂; EtOAc) to give the title compound (4.4 mg).

1H-NMR (400 MHz, CDCl₃) δ(ppm): 8.38 (d, 1H), 7.72 (d, 1H), 7.58 (t,1H), 7.35-7.07 (m, 6H), 3.34 (s, 3H), 2.86 (s, 3H), 2.73 (s, 3H) and3.3-2.7 (m, 12H).

Example 154N-(3-{2-[4-(7-Fluoro-2-methyl-5-quinolinyl)-1piperazinyl]ethyl}phenyl)acetamide(E154) 2-Methyl-5-(1-piperazinyl)-7-fluoro quinoline

A stirred mixture of piperazine (20 g), potassium carbonate (32 g),5,7-difluoro-2-methylquinoline hydrochloride (WO2002034754, 20 g) anddimethylsulfoxide (390 mL) was heated to 120° C. for 15 hours. Themixture was cooled to room temperature, diluted with water (600 mL) andextracted with 6×500 mL portions of a mixture of DCM-ether (15:85). Thecombined organic extracts were washed with water (200 mL) and brine (200mL), dried (sodium sulfate) and the solvent was partially evaporatedunder vacuum. The precipitate formed during the evaporation wasfiltered-off, washed with ether (50 mL) and dried under vacuum to givethe title compound (4.7 g, 21%).

1H-NMR (300 MHz, CDCl₃) δ(ppm): 8.27 (d, 1H), 7.27 (dd, 1H), 7.17 (dd,1H), 6.78 (dd, 2H), 3.10 (m, 4H), 3.01 (m, 4H), 2.67 (s, 3H).

7-Fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline

N,N-Diisopropylethylamine (0.07 mL; 3 eq) was added to a solution of2-methyl-5-(1-piperazinyl)-7-fluoro quinoline (0.03 g; 1 eq) and2-(3-nitrophenyl)ethyl methanesulfonate (D4) (0.033 g; 1.1 eq) indimethylformamide (1.0 mL). The reaction mixture was heated to 90° C.for 10 hours. The dark solution was cooled to room temperature andconcentrated under reduced pressure, diluted with water (3 mL) and brine(1 mL) and extracted into ethyl acetate (3×3 mL). The organic layerswere combined, dried over sodium sulfate and concentrated under reducedpressure. The crude was purified by flash chromatography on silica,eluting with a gradient from dichloromethane to dichloromethane-MeOH(98:2) affording the title compound in 88% yield (0.04 g).

MS; (ES) m/z: 395.4 [MH]⁺. C₂₂H₂₃FN₄O₂ requires 394.

3-{2-[4-(7-Fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline

A solution of7-fluoro-2-methyl-5-{4-[2-(3-nitrophenyl)ethyl]-1-piperazinyl}quinoline(0.046 g; 1 eq) in methanol (3 mL) was added dropwise to a suspension ofiron powder (0.04 g; 7 eq) and ammonium chloride (0.04 g; 7 eq) in water(3 mL). The reactants were heated at reflux for 8 hours, with additionalamounts of iron powder (total 0.04 g; 7 eq) and ammonium chloride (0.04g; 7 eq) added in 3 portions during the reaction. The reaction mixturewas cooled to room temperature and filtered using a Millipore filter.The filtrate was concentrated under reduced pressure, diluted with water(5 mL) and a saturated aqueous solution of sodium hydrogen carbonate (2mL) and extracted into ethyl acetate (3×5 mL). The combined organicextracts were dried over sodium sulfate and concentrated under reducedpressure thus obtaining the title compound in 32% yield (0.012 g).

MS; (ES) m/z: 365.4 [MH]+. C₂₂H₂₅FN₄ requires 364. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.35 (d, 1H), 7.20 (m, 1H), 6.85 (m, 2H),7.55 (m, 2H), 6.45 (m, 2H), 3.05 (bm, 4H), 2.8-2.7 (bm, 7H), 2.70 (s,3H).

N-(3-{2-[4-(7-Fluoro-2-methyl-5-quinolinyl)-1piperazinyl]ethyl}phenyl)acetamide(E154)

The title compound was prepared in 46% yield according to the generalprocedure for the preparation of amides (Method B) starting from3-{2-[4-(7-fluoro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline andacetyl chloride:

MS: (ES) m/z: 407.3 [MH⁺]. C₂₄H₂₈N₄O requires 437. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 10.48 (bs, 1H), 9.98 (s, 1H), 8.52 (bs, 1H), 7.65 (s,1H), 7.53 (bs, 1H), 7.45 (bd, 1H), 7.36 (d, 1H), 7.28 (t, 1H), 7.23 (d,1H), 6.97 (d, 1H), 3.8-3.2 (bm, 1OH), 3.06 (dd, 2H), 2.72 (s, 3H), 2.04(s, 3H).

Example 1552,2′-[(3-{2-[4-(7-chloro-2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)imino]bis(N,N-dimethylacetamide)(E155)

The title compound was isolated in 16% yield following the proceduredescribed for Example 96.

MS: (ES) m/z: 552 [MH⁺]. C₃₀H₃₉ClN₆O₂ requires 551. 1H-NMR (500 MHz,CD₃OD) δ(ppm): 9.17 (d, 1H), 7.95 (d, 1H), 7.90 (s, 1H), 7.61 (s, 1H),7.20 (t, 1H), 6.74 (d, 1H), 6.59 (s, 1H), 6.53 (d, 1H), 4.39 (s, 4H),3.81-3.62-3.41 (d-t-t, 2-4-2), 3.55 (t, 2H), 3.16-3.03 (t, 2H), 3.01 (s,3H).

Example 1561-Ethyl-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonehydrochloride (E156)

To a stirred solution of1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(Example 85, 50 mg) in DMF (1 mL) was added sodium hydride (60%, 10 mg).The mixture was stirred for 15 minutes, then iodoethane (11 □L) wasadded. The mixture was stirred for 90 minutes then diluted with methanol(5 mL) and purified by ion exchange chromatography [SCX-2; MeOH-(1MNH₃/MeOH): (100:0)→(0:100)]. The basic washings were concentrated invacuo and purified by column chromatography [SiO₂;cyclohexane-EtOAc-MeOH: (1:1:0)→(0:10:1)] and converted to thehydrochloride salt according to the description given in the generalprocedure (D6) to give the title compound (49 mg).

MS: (ES) m/z: 444 [MH⁺]. C₂₇H₃₃N₅O requires 443. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 11.4 (m, 1H) 9.0 (d, 1H), 7.9 (m, 2H), 7.8 (d, 2H), 7.5(d, 1H), 7.4 (m, 2H), 7.2 (t, 2H), 6.9 (d, 1H), 3.6 (m, 4H), 3.6-3.3 (m,10H), 3.2-3.1 (m, 4H), 3.0 (s, 3H) and 1,2 (s, 3H).

Example 1571-(1-Methylethyl)-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinonedihydrochloride (E157)

The title compound was prepared according to the procedure described forExample 156 using1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 10 mg) and2-iodopropane (13 μL). Yield 17 mg.

MS: (ES) m/z: 458 [MH⁺]. C₂₈H₃₅N₅O requires 457. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 9.00 (d, 1H), 8.05-7.95 (m, 2H), 7.85 (d, 1H), 7.55 (s,1H), 7.40 (dd, 1H), 7.32 (dd, 1H), 7.27 (t, 1H), 6.90 (d, 1H), 4.05(sext., 1H), 4.85-4.70 (m, 4H), 3.55-3.25 (m, 10H), 3.15 (t, 2H), 2.95(s, 3H) and 1.12 (d, 6H).

Example 1581-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-3-(4-pyridinylmethyl)-2-imidazolidinonedihydrochloride (E158)

The title compound was prepared according to the procedure described forExample 156 using1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 14 mg) and4-chloromethylpyridine hydrochloride (20 mg). Yield, 19 mg.

MS: (ES) m/z: 507 [MH⁺]. C₃₁H₃₄N₆O requires 506. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 9.00 (d, 1H), 8.82 (d, 2H), 8.02-7.95 (m, 2H),7.92-7.85 (m, 3H), 7.60 (s, 1H), 7.52 (d, 2H), 7.35 (t, 1H), 7.00 (d,1H), 5.67 (s, 2H), 3.92 (t, 2H), 3.67 (t, 2H), 3.58-3.30 (m, 10H), 3.17(m, 2H) and 2.92 (s, 3H).

Example 1591-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-3-(3-pyridinylmethyl)-2-imidazolidinonedihydrochloride (E159)

The title compound was prepared according to the procedure described forExample 156 using1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 14 mg) and3-chloromethylpyridine hydrochloride (20 mg). Yield, 20 mg.

MS: (ES) m/z: 507 [MH⁺]. C₃₁H₃₄N₆O requires 506. 1H-NMR (300 MHz,d₆-DMSO) δ(ppm): 8.98 (d, 1H), 8.78 (s, 1H), 8.75 (m, 1H), 8.27 (d, 1H),8.05-7.95 (m, 2H), 7.90-7.82 (m, 2H), 7.62 (s, 1H), 7.50 (m, 2H), 7.35(t, 1H), 6.98 (d, 1H), 4.57 (s, 2H), 3.87 (t, 2H), 3.71 (m, 2H),3.57-3.30 (m, 10H), 3.20 (t, 2H) and 2.95 (s, 3H).

Example 1601-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)octahydro-2H-benzimidazol-2-one(E160)

The title compound was prepared in 100% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline andoctahydro-2H-benzimidazol-2-one.

MS: (ES/+) m/z: 470 [MH⁺]. C₂₉H₃₅N₅O requires 469. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.55 (t, 1H), 7.35-7.00 (m,6H), 3.5-3.0 (m, 6H), 2.95-2.65 (m, 11H), 2.25-1.30 (m, 8H).

Example 161(S)-2-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one(E161) (S)-Hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one

(S)-2-(Aminomethyl)pyrrolidine (250 mg) and carbonyldiimidazole (400 mg,1.0 equiv.) were dissolved in DCM (50 mL). The resulting mixture wasstirred at room temperature for 18 hours, then concentrated undervacuum. The residue was purified by flash column chromatography (SPEcartridge, SiO₂), using DCM-methanol (95:5) as eluent to afford thetitle compound as colourless solid (150 mg, 50% yield).

MS: (ES/+) m/z: 127 [MH⁺]. C₆H₁₀N₂O requires 126. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 4.3 (br s, 1H), 3.7-3.8 (m, 1H), 3.65-3.55 (m 2H), 3.25(dd, 1H), 3.05 (m, 1H), 2.00-1.70 (m, 3H), 1.40 (m, 1H).

2-(3-Iodophenyl)ethanol

A solution of borane (1M, THF, 2.5 eq., 38.2 mL) was added dropwise to astirred solution of (3-iodophenyl)acetic acid (4.0 g) in THF (100 mL)cooled to 0 □C. The resulting mixture was stirred at 0 □C. for 1 h thenwarmed to room temperature and stirred for a further 3 h. The mixturewas poured into aqueous ammonium chloride solution and extracted withethyl acetate. The combined organic phases were washed with brine, dried(sodium sulfate) and concentrated. The crude was purified by columnchromatography (SPE cartridge, SiO₂), using cyclohexane-ethyl acetate(70:30) as eluent to afford the title compound (3.5 g, 92% yield).

1H-NMR (400 MHz, CDCl₃) δ(ppm): 7.5-7 (m 5H), 4.0 (m, 2H), 2.9 (m, 2H).

2-(3-Iodophenyl)ethyl methanesulfonate

Methanesulfonyl chloride (1.5 mL, 1.2 eq.) was added dropwise to astirred solution of 2-(3-iodophenyl)ethanol (3.6 g) in dichloromethane(100 mL) and diisopropylethylamine (3.8 mL, 1.5 equiv.) at 0° C. Thesolution was warmed to room temperature and stirred for 18 h. Thereaction mixture was diluted with aqueous ammonium chloride solution andextracted with dichloromethane. The organic layers were combined, washedwith aqueous sodium hydrogencarbonate solution, brine, dried over sodiumsulfate and concentrated under reduced pressure. The crude was purifiedusing column chromatography (SiO₂ cartridge) using DCM-cyclohexane(70:30) to afford the title compound (3.2 g, 45% yield).

1H-NMR (400 MHz, CDCl₃) δ(ppm): 7.58 (m, 2H), 7.25-7.0 (m, 2H), 4.48 (t,2H), 3.0 (t, 3H).

5-{4-[2-(3-Iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline

N,N-Diisopropylethylamine (1.7 mL; 1.5 eq) was added to a solution of2-methyl-5-(1-piperazinyl)quinoline (D3) (1.31 g; 0.9 eq) and2-(3-iodophenyl)ethyl methanesulfonate (2.1 g) in dimethylformamide (20mL). The reaction mixture was heated to 90° C. for 5 hours. The darksolution was concentrated under reduced pressure, and purified byion-exchange chromatography (SCX-2), eluting withmethanol-ammonia/methanol (1M), (1:0) to (0:1). The combined basicfractions were concentrated under vacuum and purified by columnchromatography (SPE cartridge, SiO₂) using dichloromethane-methanol(95:5) to afford the title compound (1.5 g, 60% yield).

MS; (ES) m/z: 457, 459 [MH]⁺. C₂₂H₂₄IN₃ requires 457. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.5 (d, 1H), 7.6-7.5 (m, 3H), 7.3-7.0 (m,4H), 3.1 (m, 4H), 2.85-2.65 (m, 11H).

(S)-2-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one(E161)

The title compound was prepared in 60% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and(S)-hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one.

MS: (ES/+) m/z: 456 [MH⁺]. C₂₈H₃₃N₅O requires 455. 1H-NMR (400 MHz,CDCl₃) δ(ppm): 10.68 (v br s, 1H), 8.82 (v br s, 1H), 7.88 (br s, 2H),7.76 (br s, 1H), 7.66 (s, 1H), 7.47 (d, 1H), 7.40 (br s, 1H), 7.34 (t,3H), 7.00 (d, 1H), 4.10-3.0 (v br m, 17H), 2.86 (br s, 3H), 2.1-1.37 (m,4H).

Example 162(R)-2-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one(E162) (R)-(1,1-Dimethylethyl2-{[(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)amino]methyl}-1-pyrrolidinecarboxylate

3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 115 mg)and N-(tert-butoxycarbonyl)-L-prolinal (1.2 equiv., 79 mg) were stirredin methanol (2 mL) until the mixture became a clear solution. Then,sodium triacetoxyborohydride (1.2 eq., 85 mg) was added. After 24 h thereaction mixture was loaded onto an ion-exchange cartridge (SCX-2) andeluted with methanol followed by ammonia/methanol (1M). The combinedbasic fractions were concentrated in vacuo and purified by columnchromatography (SPE cartridge, silica) using DCM-methanol (95:5) aseluent to afford the title compound (70 mg, 40% yield).

MS: (ES/+) m/z: 530 [MH⁺]. C₃₂H₄₃N₅O₂ requires 529. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.70 (d, 1H), 7.2 (d, 1H), 7.15-7.00 (m,2H), 6.5 (br m, 3H), 4.00-2.90 (v br m, 20H) (m, 4H), 2.00-1.50 (vr b m,13H).

(R)-2-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)hexahydro-3H-pyrrolo[1,2-c]imidazol-3-one(E162)

A solution of (R)-(1,1-dimethylethyl2-{[(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)amino]methyl}-1-pyrrolidinecarboxylatein methanol was treated with a solution of hydrogen chloride in ether (1M). The resulting mixture was stirred 30 minutes then concentrated undervacuum and then loaded onto an ion-exchange cartridge (SCX-2) and elutedwith methanol followed by ammonia in methanol (1 M). The combined basicfractions were concentrated under vacuum. The residue, (10 mg) was thendissolved in DCM (1 mL) and treated with triphosgene (23 mg, 0.3 eq.),diisopropylamine (4 uL, 3 eq.). The mixture was stirred for 1 h thenconcentrated under vacuum and purified by preparative mass-directed hplcto afford the title compound (3.1 mg).

MS: (ES/+) m/z: 456 [MH⁺]. C₂₈H₃₃N₅O requires 455. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.35 (d, 1H), 7.75 (d, 1H), 7.65 (s, 1H), 7.60 (d, 1H),7.20-7.35 (m, 3H), 7.30 (d, 1H), 6.95 (d, 1H), 6.5 (br m, 3H), 4.00-2.90(v br m, 12H) 2.85 (s, 3H), 2.00-1.50 (m, 4H).

Example 1635,5-Dimethyl-1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(E163) 4,4-Dimethyl-2-imidazolidinone

A solution of (2-amino-1,1-dimethylethyl)amine (1.0 g) and1,1′-carbonylimidazole (1.9 g, 1.0 equiv.) in DCM (50 mL) was stirredfor 18 hours then concentrated and purified using column chromatography(SPE cartridge, SiO₂), using DCM-methanol (95:5) as eluent to afford thetitle compound as colourless solid (1.0 g, 83% yield).

MS: (ES/+) m/z: 115 [MH⁺]. C₅H₁₀N₂O requires 114. 1H-NMR (300 MHz,CDCl₃) δ (ppm): 4.5 (br s, 1H), 3.25 (s, 2H), 1.25 (s, 6H).

5,5-Dimethyl-1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone(E163)

The title compound was prepared in 87% yield according to the generalprocedure for the preparation of the amides, ureas and carbamates(Method A) starting from5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and4,4-dimethyl-2-imidazolidinone.

MS: (ES/+) m/z: 444 [MH⁺]. C₂₇H₃₃N₅O requires 443. 1H-NMR (400 MHz,CDCl₃) δ(ppm): 10.89 (br s, 1H), 8.87 (br s, 1H), 7.92 (br s, 2H),7.58(dd, 1H), 7.4 (br s, 1H), 7.44 (dd, 1H), 7.3(t, 1H), 7.21 (s, 1H),6.95 (d, 1H), 3.74 (dd, 2H), 3.61 (s, 2H), 3.60-3.30 (m, 8H), 2.87 (s,3H), 1.3 (s, 6H).

Example 164 (R or S)1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-2-imidazolidinone(E164)

Racemic1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-2-imidazolidinonewas prepared in 41% yield according to the general procedure for thepreparation of the amides, ureas and carbamates (Method A) starting from5-{4-[2-(3-bromophenyl)propyl]-1-piperazinyl}-2-methylquinoline (D20)and 2-imidazolidinone.

The racemate was separated using preparative chiral HPLC (DaicelChiralcel OD column), eluting with n-hexane-ethanol (60:40) to affordthe title compound as the first-eluting enantiomer.

MS: (ES/+) m/z: 430 [MH⁺]. C₂₆H₃₁N₅O requires 429. 1H-NMR (500 MHz,d₆-DMSO) δ (ppm): 10.62 (br s, 1H), 8.94 (br s, 1H), 7.88 (br s, 2H),7.75 (br s, 1H), 7.58 (s, 1H), 7.50-6.90 (m, 4H), 6.08 (br s, 1H),3.90-2.70 (br m, 15H), 2.85 (brs, 3H), 1.22 (d, 3H).

Example 165 (S or R)1-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-2-imidazolidinone(E165)

The title compound was prepared according to the method described forExample 164, and was isolated as the second-eluting enantiomer.

MS: (ES/+) m/z: 430 [MH⁺]. C₂₆H₃₁N₅O requires 429. 1H-NMR (500 MHz,d₆-DMSO) δ (ppm): 10.62 (br s, 1H), 8.94 (br s, 1H), 7.88 (br s, 2H),7.75 (br s, 1H), 7.58 (s, 1H), 7.50-6.90 (m, 4H), 6.08 (br s, 1H),3.90-2.70 (br m, 15H), 2.85 (brs, 3H), 1.22 (d, 3H).

Example 166N-(3-{3-[4-(2-Methyl-quinolin-5-yl)-piperazin-1-yl]-propyl}-phenyl)-methanesulfonamide(E166) N-(3-Iodo-phenyl)-methanesulfonamide

To a stirred solution of 3-iodoaniline (1.99 g, 9.1 mmol) in anhydrouspyridine (20 mL) at 0° C. was added methanesulfonic anhydride (1.92 g,11 mmol) in small portions. The resulting mixture was stirred whilewarming from 0° C. to room temperature until all the aniline wasconsumed. The pyridine was removed in vacuo. The residue was partitionedbetween dichloromethane (100 mL) and saturated aqueous sodiumhydrogencarbonate solution (100 mL). The organic layer was dried (sodiumsulfate) and evaporated in vacuo. The crude product was purified bysilica gel chromatography (ethyl acetate in hexane, 10% to 30%) to givethe title compound as a yellow solid (2.38 g, 89%).

Mass spectrum (API−): Found 296 ([M−H]⁻). C₇H₈INO₂S requires 297. 1H NMR(CDCl₃) δ (ppm): 3.04 (3H, s), 6.42 (1H, br. s), 7.08 (1H, m), 7.22 (1H,m), 7.53 (1H, m), 7.56 (1H, s).

N-[3-(3-Oxo-propyl)-phenyl]-methanesulfonamide

A mixture of N-(3-iodo-phenyl)-methanesulfonamide (2.4 g, 8 mmol),tetra-n-butyl-ammonium chloride (2.22 g, 8 mmol), allyl alcohol (0.7 g,12 mmol), sodium hydrogencarbonate (1.6 g, 19 mmol) andpalladium(II)chloride (0.36 g, 1.8 mmol) in anhydrous dimethylformamide(30 mL) was stirred at room temperature for 48 h under argon. Themixture was then diluted with 5% aqueous hydrochloric acid (100 mL) andextracted with ethyl acetate (2×100 mL). The combined organic layerswere dried (sodium sulfate) and evaporated in vacuo. The crude productwas purified by silica gel chromatography (ethyl acetate in hexane, 30%to 50%) to give the title compound as an amber oil (1.1 g, 60%).

Mass spectrum (API−): Found 226 ([M−H]⁻). C₁₀H₁₃NO₃S requires 227. 1HNMR (CDCl₃) δ (ppm): 2.80 (2H, m), 2.96 (2H, t, J=8Hz), 3.01 (3H, s),6.46 (1H, br. s), 7.00-7.10 (3H, m), 7.28 (1H, t, J=8 Hz), 9.82 (1H, s).

N-(3-{3-[4-(2-Methyl-quinolin-5-yl)-piperazin-1-yl]-propyl}-phenyl)-methanesulfonamide(E166)

The title compound was prepared fromN-[3-(3-oxo-propyl)-phenyl]-methanesulfonamide and of2-methyl-5-(1-piperazinyl)quinoline (D3) according to the methods inDescription 4 and Description 5.

Mass spectrum (API−): Found 437 ([M−H]⁻). C₂₄H₃₀N₄O₂S requires 438. 1HNMR (CDCl₃) δ (ppm): 1.91 (2H, m), 2.50 (2H, m), 2.71 (6H, m), 2.73 (3H,s), 3.02 (3H, s), 3.12 (4H, m), 6.30 (1H, br. s), 7.00-7.10 (4H, m),7.26 (2H, m), 7.58 (1H, t, J=8 Hz), 7.72 (1H, d, J=8Hz), 8.28 (1H, d,J=8 Hz).

Example 1674-(3-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(E167)

The title compound was obtained as a mixture (85:15) with theregioisomer2-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,2-dihydro-3H-1,2,4-triazol-3-onefollowing the general procedure for the preparation of amides, ureas andcarbamates (Method A) starting from5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and1,2-dihydro-3H-1,2,4-triazol-3-one.

MS: (ES/+) m/z: 415 [MH⁺]. C₂₄H₂₆N₆O requires 414. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 11.92 (bs, 1H), 8.32 (d, 1H), 8.30 (d, 1H), 7.55 (br s,1H), 7.53 (m, 2H), 7.48 (dd, 1H), 7.37 (t, 1H), 7.34 (d, 1H), 7.22 (d,1H), 7.05 (dd, 1H), 7.05 (dd, 1H), 2.99 (br s, 4h), 2.85-2.6 (m, 10H),2.58 (s, 4H).

Example 1685-methyl-2-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dihydro-3H-pyrazol-3-one(E168)

The title compound was prepared in 58% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and5-methyl-2,4-dihydro-3H-pyrazol-3-one.

MS: (ES/+) m/z: 428 [MH⁺]. C₂₆H₂₉N₅O requires 427. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.30 (d, 1H), 7.65 (m, 2H), 7.50 (t, 1H), 7.27-7.16 (m,3H), 7.01-6.98 (m, 2H) 3.08 (m, 4H), 2.90-2.60 (m, 14H), 2.14 (s, 2H).

Example 1692-(4-Fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-5-methyl-2,4-dihydro-3H-pyrazol-3-one(E169)

The title compound was prepared in 92% yield according to the generalprocedure for the preparation of amides, ureas and carbamates (Method A)starting from5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and5-methyl-2,4-dihydro-3H-pyrazol-3-one.

MS: (ES/+) m/z: 446 [MH⁺]. C₂₆H₂₈FN₅O requires 445. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.30 (d, 1H), 7.71-7.59 (m, 3H), 7.50 (t, 1H), 7.17 (d,1H), 7.0-6.4 (m, 2H), 3.35 (s, 2H), 3.05 (m, 4H), 2.88-2.64 (m, 11H),2.13 (s, 2H).

Example 1705-(4-{2-[3-(5,6-dihydro-7H-imidazo[2,1-c][1,2,4]triazol-7-yl)phenyl]ethyl}-1-piperazinyl)-2-methylquinoline(E170) 5,6-Dihydro-1H-imidazo[2,1-c][1,2,4]triazole

2-Hydrazino-2-imidazoline hydrobromide (200 mg) was suspended in ethylorthoformate (2 ml) and stirred at 150° C. under microwave irradiationfor 10 min. The reaction mixture was cooled to room temperature thendiluted with methanol and loaded onto an ion-exchange column (SCX-2),which was eluted with methanol followed by ammonia-methanol solution(1M). The combined basic fractions were concentrated under vacuum andpurified using column chromatography [SiO₂; DCM-MeOH (90:10)] to affordthe title compound as colourless solid (60 mg, 60% yield).

MS: (ES/+) m/z: 112 [MH⁺]. C₄H₆N₄ requires 111. 1H-NMR (300 MHz, CDCl₃)δ(ppm): 7.95 (s, 1H), 6.25 (s, 1H), 3.95 (m, 4H).

5-(4-{2-[3-(5,6-Dihydro-7H-imidazo[2,1-c][1,2,4]triazol-7-yl)phenyl]ethyl}-1-piperazinyl)-2-methylquinoline(E170)

5-{4-[2-(3-Iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline (59 mg),5,6-dihydro-1H-imidazo[2,1-c][1,2,4]triazole (50 mg, 3.5 equiv.),palladium(II)acetate (9 mg, 0.3 equiv.)2-(dicyclohexylphosphino)-2′-methylbiphenyl (42 mg, 0.9 equiv.) andpotassium phosphate (97 mg, 3.5 equiv.) were suspended in DME andstirred at 150 □C. under microwave irradiation for 2 h. The mixture wascooled to room temperature, diluted with methanol and loaded onto anion-exchange cartridge (SCX-2), which was eluted with methanol followedby ammonia-methanol solution (1M). The combined basic fractions wereconcentrated under vacuum and purified using column chromatography[SiO₂; DCM-MeOH (90:10)] to afford the title compound as colourlesssolid (13 mg, 26% yield).

MS: (ES/+) m/z: 440 [MH⁺]. C₂₆H₂₉N₇ requires 439. 1H-NMR (300 MHz,CDCl₃) δ(ppm): 8.40 (d, 1H), 7.90 (s, 1H), 7.70 (d, 1H), 7.6-7.5 (m,2H), 7.35-7.20 (m, 3H), 7.1 (d, 1H), 6.9(d, 1H), 4.55 (t, 2H), 4.28 (t,2H), 3.15 (m, 4H), 3.0-2.7 (m, 11H).

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein: R₁ is halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy orhaloC₁₋₆alkyl; m is 0, 1, 2, 3 or 4; X is N or CH; R₂ is halogen, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy or haloC₁₋₆alkyl; n is 0, 1 or 2;W is —CH₂—, —CH(C₁₋₆alkyl)- or —C(C₁₋₆alkyl)(C₁₋₆alkyl)-; p is 0, 1, 2or 3; Y and Z together form a C₃₋₇cycloalkylene group, or Y is —CH₂—,—CH(C₁₋₆alkyl)- or —C(C₁₋₆alkyl)(C₁₋₆alkyl) and Z is —CH₂—, —CHOH—,—CHR₆— or —CR₆R₇— (wherein R₆ and R₇ are independently halogen, cyano,C₁₋₆alkyl or C₁₋₆alkoxy); R₃ and R₄ are independently hydrogen,C₁₋₆alkyl, C₁₋₆alkylsulfonyl or a group having the formula (II):

 wherein r is 0, 1, 2, 3 or 4; A is oxygen or sulfur; B is a single bondor —NR₈— (wherein R₈ is hydrogen, C₁₋₆alkyl or aryl, wherein the aryl isoptionally substituted by one or more substituents independentlyselected from halogen, oxo, C₁₋₆alkyl, CF₃, cyano, hydroxy,C₁₋₆alkanoyl, and C₁₋₆alkoxy); D is —(CH₂)_(t)—, —(CH₂)_(t)O— or—O(CH₂)_(t)—, wherein t is 0, 1, 2, 3 or 4; and E is C₁₋₆alkyl,haloC₁₋₆alkyl, C₃₋₇cycloalkyl (optionally substituted by one or moresubstituents independently selected from halogen, hydroxy, oxo,C₁₋₆alkyl, cyano, CF₃, OCF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl), aryl(optionally substituted by one or more substituents independentlyselected from halogen, oxo, C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyland C₁₋₆alkoxy), or E is —NR₉R₁₀, wherein R₉ and R₁₀ are independentlyselected from hydrogen, C₁₋₆alkyl and aryl (optionally substituted byone or more substituents independently selected from halogen, oxo,C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl and C₁₋₆alkoxy); or R₃ andR₄, together with the nitrogen atom to which R₃ and R₄ are attached,form an optionally substituted 3-7 membered monocyclic heterocyclicgroup or an optionally substituted 8-11 membered bicyclic heterocyclicgroup, selected from the list consisting of aziridinyl, azetidinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl,thiazolidinyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, piperidyl, piperazinyl, morpholinyl, thiazinanyl,azepinyl, azepanyl, 6H-thieno[2,3-b]pyrrolyl,imidazo[2,1-b][1,3]thiazolyl, imidazo[5,1-b][1,3]thiazolyl, indolyl,isoindolyl, indazolyl, benzimidazolyl, decahydroquinolinyl,octahydro-2H-1,4-benzoxazinyl, octahydro-1H-cyclopenta[b]pyridinyl,indolinyl, isoindolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,benzoxazinyl, 2,3-dihydro-1,4-benzoxazinyl and benzoazepinyl; whereinthe heterocyclic groups formed may be substituted by one or moresubstituents, which may be the same or different, and which are selectedfrom halogen, oxo, C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryland arylC₁₋₆alkyl (wherein the aryl and the arylC₁₋₆alkyl are furtheroptionally substituted by halogen, oxo, C₁₋₆alkyl, cyano, CF₃,C₁₋₆alkoxy or C₁₋₆alkanoyl); and R₅ is independently halogen, cyano,C₁₋₆alkyl or C₁₋₆alkoxy; and q is 0, 1, 2, 3 or 4;  wherein the arylgroup is selected from the list consisting of is phenyl, pyrrolyl,imidazolyl, pyrazolyl, isothiazolyl, thiazolyl, isoxazolyl, furazanyl,furyl, thienyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, naphthyl,indenyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl,benzothienyl, benzuforanyl, dihydrobenzofuranyl, tetrahydrobenzofuranyl,quinolyl, quinoxalinyl, quinazolinyl, isoquinolyl, indazylyl, indanyl,tetrahydronaphthyl, indolinyl, isoindolinyl, tetrahydroisoquinolinyl,tetrahydroquinolyl, benzoxazinyl and benzoazepinyl.
 2. A compound asclaimed in claim 1 wherein, R₃ and R₄, together with the nitrogen atomto which R₃ and R₄ are attached, form a 3-7 membered monocyclicheterocyclic group selected from

R₃ and R₄, together with the nitrogen atom to which R₃ and R₄ areattached, form a 8-11 membered bicyclic heterocyclic group, selectedfrom

wherein w is 0, 1, 2, 3 or 4 and R is independently halogen, oxo,C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryl or arylC₁₋₆alkyl,wherein the aryl and the arylC₁₋₆alkyl are further optionallysubstituted by one or more halogen, oxo, C₁₋₆alkyl, cyano, CF₃,C₁₋₆alkoxy or C₁₋₆alkanoyl.
 3. A compound as claimed in claim 1, whereinn is 0 or n is 1 and R₂ is C₁₋₆alkyl.
 4. A compound as claimed in claim1, wherein p is
 0. 5. A compound as claimed in claim 1, wherein Y and Zare independently —CH₂—, —CH(CH₃)— or —CH(OH)—.
 6. A compound as claimedin claim 1, wherein formula (II) is:

wherein A is oxygen or sulfur, D is —(CH₂)_(t)—, —(CH₂)_(t)O— or—O(CH₂)_(t)—, wherein t is 0, 1, 2, 3 or 4 and E is C₁₋₆alkyl,C₃₋₇cycloalkyl (optionally substituted by one or more substituentsindependently selected from halogen, hydroxy, oxo, C₁₋₆alkyl, cyano,CF₃, OCF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl), or aryl (optionally substitutedby one or more substituents independently selected from halogen,C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy); or

wherein A is oxygen or sulfur, D is —(CH₂)_(t)—, —(CH₂)_(t)O— or—O(CH₂)_(t)—, wherein t is 0, 1, 2, 3 or 4 and E is C₁₋₆alkyl,C₃₋₇cycloalkyl (optionally substituted by one or more substituentsindependently selected from halogen, hydroxy, oxo, C₁₋₆alkyl, cyano,CF₃, OCF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl), or aryl (optionally substitutedby one or more substituents independently selected from halogen,C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy).
 7. Acompound as claimed in claim 1, wherein E is a 5- to 7-memberedmonocyclic aromatic ring wherein one or more of the carbon atoms in thering is optionally replaced by a heteroatom independently selected fromnitrogen, oxygen and sulfur, wherein the ring is optionally substitutedby one or more substituents independently selected from oxo, halogen,C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy; or E is a9- to 10-membered bicyclic aromatic ring, wherein one or more of thecarbon atoms in the ring is optionally replaced by a heteroatomindependently selected from nitrogen, oxygen and sulfur, wherein thering is optionally substituted by one or more substituents independentlyselected from oxo, halogen, C₁₋₆alkyl, CF₃, cyano, hydroxy,C₁₋₆alkanoyl, and C₁₋₆alkoxy.
 8. A compound as claimed in claim 1,wherein E is methylamine, ethylamine, propylamine, isopropylamine,butylamine, isobutylamine, sec-butylamine, tert-butylamine, pentylamine,neopentylamine, sec-pentylamine, n-pentylamine, isopentylamine,tert-pentylamine, hexylamine; dimethylamine, diethylamine,dipropylamine, diisopropylamine, dibutylamine, diisobutylamine,disec-butylamine, ditert-butylamine, dipentylamine, dineopentylamine,dihexylamine, butylmethylamino, isopropylmethylamino,ethylisopropylamino, ethylmethylamino, a monoarylamino or amonoC₁₋₆alkyl-monoarylamino.


9. A compound as claimed in claim 1, having a general formula (Ia):wherein: R₁ is halogen, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, haloC₁₋₆alkoxy orhaloC₁₋₆alkyl; m is 0, 1, 2, 3 or 4; X is N or CH; p is 1, 2, 3 or 4; Yis —CH₂—, —CH(C₁₋₆alkyl)- or —C(C₁₋₆alkyl)(C₁₋₆alkyl)-; Z is —CH₂—,—CHOH—, —CHR₆— or —CR₆R₇—, wherein R₆ and R₇ are independently halogen,cyano, C₁₋₆alkyl or C₁₋₆alkoxy; R₃ and R₄ are independently hydrogen,C₁₋₆alkyl, C₁₋₆alkylsulfonyl or a group having the formula (II):

wherein: r is 0, 1, 2, 3 or 4; A is oxygen or sulfur; B is a single bondor —NR₈— wherein R₈ is hydrogen, C₁₋₆alkyl or aryl optionallysubstituted by one or more substituents independently selected fromhalogen, oxo, C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋ ₆alkanoyl, andC₁₋₆alkoxy; D is —(CH₂)_(t)—, —(CH₂)_(t)O— or —O(CH₂)_(t)—, wherein t is0, 1, 2, 3 or 4; and E is C₁₋₆alkyl, haloC₁₋₆alkyl, C₃₋₇cycloalkyl(optionally substituted by one or more halogen, hydroxy, oxo, C₁₋₆alkyl,cyano, CF₃, OCF₃, C₁₋₆alkoxy or C₁₋₆alkanoyl), or aryl (optionallysubstituted by one or more substituents independently selected fromhalogen, oxo, C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, andC₁₋₆alkoxy); or E is —NR₉R₁₀ (wherein R₉ and R₁₀ are independentlyselected from hydrogen, C₁₋₆alkyl and aryl optionally substituted by oneor more substituents independently selected from halogen, oxo,C₁₋₆alkyl, CF₃, cyano, hydroxy, C₁₋₆alkanoyl, and C₁₋₆alkoxy); or R₃ andR₄, together with the nitrogen atom to which R₃ and R₄ are attached,form an optionally substituted 3-7 membered monocyclic heterocyclicgroup selected from the list consisting of aziridinyl, azetidinyl,pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl,thiazolidinyl, pyrrolyl, pyrrolinyl, pyrazolinyl, imidazolyl, pyrazolyl,triazolyl, tetrazolyl, piperidyl, piperazinyl, morpholinyl, thiazinanyl,azepinyl and azepanyl; and R₅ is independently halogen, cyano, C₁₋₆alkylor C₁₋₆alkoxy; and q is 0, 1, 2, 3 or
 4. 10. A compound as claimed inclaim 9 wherein, R₃ and R₄, together with the nitrogen atom to which R₃and R₄ are attached, combine to form a 3-7 membered monocyclicheterocyclic group selected from

wherein w is 0, 1, 2, 3 or 4 and R is independently halogen, oxo,C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy, C₁₋₆alkanoyl, aryl or arylC₁₋₆alkylwherein the aryl and the arylC₁₋₆alkyl are further optionallysubstituted by one or more substituents selected from halogen, oxo,C₁₋₆alkyl, cyano, CF₃, C₁₋₆alkoxy and C₁₋₆alkanoyl.
 11. A compound asclaimed in claim 1, which is:3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one;N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-N′-phenylurea;N-[2-(methyloxy)phenyl]-N′-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)urea;2,4-dimethyl-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-thiazole-5-carboxamide;N-(3-{1-hydroxy-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-dimethyl-1,3-thiazole-5-carboxamide;2-fluoro-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide;3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]propyl}phenyl)-1,3-oxazolidin-2-one;3-(3-{2-[(2R)-2-methyl-4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one;1-methyl-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone;1-(4-fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone;3-(4-fluoro-3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-oxazolidin-2-one;1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,4-imidazolidinedione;1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-one;1-methyl-3-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-1,3-dihydro-2H-imidazol-2-one;4,4-dimethyl-1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone;or a pharmaceutically acceptable salt thereof.
 12. A method of treatmentof depression or anxiety in a mammal including a human, which comprisesadministering to the sufferer a therapeutically safe and effectiveamount of a compound as claimed in claim
 1. 13. A pharmaceuticalcomposition comprising a compound as claimed in claim 1, and apharmaceutically acceptable carrier or excipient.
 14. A process forpreparing a pharmaceutical composition as defined in claim 13, theprocess comprising mixing a compound as claimed in claim 1 and apharmaceutically acceptable carrier or excipient.